neuronal acetylcholine receptor subunit beta-4 isoform X4 [Homo sapiens]
Protein Classification
ligand-gated ion channel; ligand-gated ion channel family protein( domain architecture ID 1903392)
ligand-gated ion channel (LIC or LGIC) is a member of a family of neurotransmitter receptors vital for communication throughout the nervous system; similar to acetylcholine receptor subunits; ligand-gated ion channel family protein similar to neurotransmitter-gated ion channels such as nicotinic acetylcholine receptor (nAChR), serotonin 5-hydroxytryptamine receptor (5-HT3), type-A gamma-aminobutyric acid receptor (GABAAR) and glycine receptor (GlyR)
List of domain hits
| Name | Accession | Description | Interval | E-value | |||||||
| LGIC_ECD super family | cl28912 | extracellular domain (ECD) of Cys-loop neurotransmitter-gated ion channels (also known as ... |
54-231 | 2.25e-138 | |||||||
extracellular domain (ECD) of Cys-loop neurotransmitter-gated ion channels (also known as ligand-gated ion channel (LGIC)); This superfamily contains the extracellular domain (ECD) of Cys-loop neurotransmitter-gated ion channels, which include nicotinic acetylcholine receptor (nAChR), serotonin 5-hydroxytryptamine receptor (5-HT3), type-A gamma-aminobutyric acid receptor (GABAAR) and glycine receptor (GlyR). These ligand-gated ion channels (LGICs) are found across metazoans and have close homologs in bacteria. They are vital for communication throughout the nervous system. GABAAR and GlyR are anionic channels, both mediating fast inhibitory synaptic transmission. Cl- ions are selectively conducted through the GABAAR receptor pore, resulting in hyperpolarization of the neuron. nAChR is a non-selective cation channel that is permeable to Na+ and K+, and some subunit combinations are also permeable to Ca2+. Na+ enters and K+ exits to allow net flow of positively charged ions inward. 5-HT3, a cation-selective channel, binds serotonin and is permeable to Na+, K+, and Ca2+. It mediates neuronal depolarization and excitation within the central and peripheral nervous systems. These ligand-gated chloride channels are critical not only for maintaining appropriate neuronal activity, but have long been important therapeutic targets: benzodiazepines, barbiturates, some intravenous and volatile anaesthetics, alcohol, strychnine, picrotoxin, and ivermectin all derive their biological activity from acting on the inhibitory half of the Cys-loop receptor family. The ECD contains the ligand binding sites for these receptors. The actual alignment was detected with superfamily member cd19027: Pssm-ID: 475126 Cd Length: 178 Bit Score: 394.75 E-value: 2.25e-138
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| LIC super family | cl42365 | Cation transporter family protein; The Ligand-gated Ion Channel (LIC) Family of ... |
5-419 | 4.28e-85 | |||||||
Cation transporter family protein; The Ligand-gated Ion Channel (LIC) Family of Neurotransmitter Receptors TC 1.A.9)Members of the LIC family of ionotropic neurotransmitter receptors are found only in vertebrate and invertebrate animals. They exhibit receptor specificity for (1)acetylcholine, (2) serotonin, (3) glycine, (4) glutamate and (5) g-aminobutyric acid (GABA). All of these receptor channels are probably hetero- orhomopentameric. The best characterized are the nicotinic acetyl-choline receptors which are pentameric channels of a2bgd subunit composition. All subunits arehomologous. The three dimensional structures of the protein complex in both the open and closed configurations have been solved at 0.9 nm resolution.The channel protein complexes of the LIC family preferentially transport cations or anions depending on the channel (e.g., the acetylcholine receptors are cationselective while glycine receptors are anion selective). [Transport and binding proteins, Cations and iron carrying compounds] The actual alignment was detected with superfamily member TIGR00860: Pssm-ID: 455710 [Multi-domain] Cd Length: 459 Bit Score: 268.51 E-value: 4.28e-85
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| Name | Accession | Description | Interval | E-value | |||||||
| LGIC_ECD_nAChR_B4 | cd19027 | extracellular domain of nicotinic acetylcholine receptor subunit beta 4 (CHRNB4); This ... |
54-231 | 2.25e-138 | |||||||
extracellular domain of nicotinic acetylcholine receptor subunit beta 4 (CHRNB4); This subfamily contains the extracellular domain of nicotinic acetylcholine receptor subunit beta 4 (beta4), encoded by the CHRNB4 gene and ubiquitously expressed on lung epithelial cells. The cluster of human neuronal nicotinic receptor gene CHRNA5-CHRNA3-CHRNB4 is related to drug-related behaviors and the development of lung cancer. One of the most broadly expressed subtype is the alpha-3 beta-4 nAChR, also known as the ganglion-type nicotinic receptor, located in the autonomic ganglia and adrenal medulla, where activation yields post- and/or pre-synaptic excitation, mainly by increased Na+ and K+ permeability. Beta4 forms heteromeric nAchRs to modulate receptor affinity for nicotine, but the exact pentameric stochiometry of alpha3beta4 receptor is not known; functional assemblies with varying subunit stoichiometries are possible. Pssm-ID: 349828 Cd Length: 178 Bit Score: 394.75 E-value: 2.25e-138
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| Neur_chan_LBD | pfam02931 | Neurotransmitter-gated ion-channel ligand binding domain; This family is the extracellular ... |
27-232 | 2.50e-93 | |||||||
Neurotransmitter-gated ion-channel ligand binding domain; This family is the extracellular ligand binding domain of these ion channels. This domain forms a pentameric arrangement in the known structure. Pssm-ID: 460752 [Multi-domain] Cd Length: 215 Bit Score: 281.08 E-value: 2.50e-93
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| LIC | TIGR00860 | Cation transporter family protein; The Ligand-gated Ion Channel (LIC) Family of ... |
5-419 | 4.28e-85 | |||||||
Cation transporter family protein; The Ligand-gated Ion Channel (LIC) Family of Neurotransmitter Receptors TC 1.A.9)Members of the LIC family of ionotropic neurotransmitter receptors are found only in vertebrate and invertebrate animals. They exhibit receptor specificity for (1)acetylcholine, (2) serotonin, (3) glycine, (4) glutamate and (5) g-aminobutyric acid (GABA). All of these receptor channels are probably hetero- orhomopentameric. The best characterized are the nicotinic acetyl-choline receptors which are pentameric channels of a2bgd subunit composition. All subunits arehomologous. The three dimensional structures of the protein complex in both the open and closed configurations have been solved at 0.9 nm resolution.The channel protein complexes of the LIC family preferentially transport cations or anions depending on the channel (e.g., the acetylcholine receptors are cationselective while glycine receptors are anion selective). [Transport and binding proteins, Cations and iron carrying compounds] Pssm-ID: 273305 [Multi-domain] Cd Length: 459 Bit Score: 268.51 E-value: 4.28e-85
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| Neur_chan_memb | pfam02932 | Neurotransmitter-gated ion-channel transmembrane region; This family includes the four ... |
239-447 | 3.36e-65 | |||||||
Neurotransmitter-gated ion-channel transmembrane region; This family includes the four transmembrane helices that form the ion channel. Pssm-ID: 460753 [Multi-domain] Cd Length: 232 Bit Score: 209.43 E-value: 3.36e-65
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| LGIC_TM_nAChR | cd19064 | transmembrane domain of nicotinic acetylcholine receptor (nAChR); This family contains ... |
233-322 | 1.92e-45 | |||||||
transmembrane domain of nicotinic acetylcholine receptor (nAChR); This family contains transmembrane (TM) domain of the nicotinic acetylcholine receptor (nAChR). The transmembrane region consists of four transmembrane-spanning alpha-helical segments (M1-M4) that are linked by loops. The intracellular loop that links M1 and M2 determines the ion selectivity of the channel. nAChR is found in high concentrations at the nerve-muscle synapse, where it mediates fast chemical transmission of electrical signals in response to the endogenous neurotransmitter acetylcholine (ACh) released from the nerve terminal into the synaptic cleft. Thus far, seventeen nAChR subunits have been identified, including ten alpha subunits, four beta subunits and one gamma, delta, and epsilon subunit each, all found on the cell membrane that non-selectively conducts cations (Na+, K+, Ca++). These nAChR subunits combine in several different ways to form functional nAChR subtypes which are broadly categorized as either muscle subtype located at the neuromuscular junction or neuronal subtype that are found on neurons and on other cell types throughout the body. The muscle type of nAChRs are formed by the alpha1, beta1, gamma, delta, and epsilon subunits while the neuronal type are composed of nine alpha subunits and three beta subunits, which combine in various permutations and combinations to form functional receptors. Among various subtypes of neuronal nAChRs, the homomeric alpha7 and the heteromeric alpha4beta2 receptors are the main subtypes widely distributed in the brain and implicated in the pathophysiology of neurodevelopmental disorders such as schizophrenia and autism and neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease. Among subtypes of muscle nAChRs, the heteromeric subunits (alpha1)2, beta, gamma, and delta in fetal muscle, and the gamma subunit replaced by epsilon in adult muscle have been implicated in congenital myasthenic syndromes and multiple pterygium syndromes due to various mutations. This family also includes alpha- and beta-like nAChRs found in protostomia. Pssm-ID: 349866 [Multi-domain] Cd Length: 113 Bit Score: 153.82 E-value: 1.92e-45
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| Name | Accession | Description | Interval | E-value | |||||||
| LGIC_ECD_nAChR_B4 | cd19027 | extracellular domain of nicotinic acetylcholine receptor subunit beta 4 (CHRNB4); This ... |
54-231 | 2.25e-138 | |||||||
extracellular domain of nicotinic acetylcholine receptor subunit beta 4 (CHRNB4); This subfamily contains the extracellular domain of nicotinic acetylcholine receptor subunit beta 4 (beta4), encoded by the CHRNB4 gene and ubiquitously expressed on lung epithelial cells. The cluster of human neuronal nicotinic receptor gene CHRNA5-CHRNA3-CHRNB4 is related to drug-related behaviors and the development of lung cancer. One of the most broadly expressed subtype is the alpha-3 beta-4 nAChR, also known as the ganglion-type nicotinic receptor, located in the autonomic ganglia and adrenal medulla, where activation yields post- and/or pre-synaptic excitation, mainly by increased Na+ and K+ permeability. Beta4 forms heteromeric nAchRs to modulate receptor affinity for nicotine, but the exact pentameric stochiometry of alpha3beta4 receptor is not known; functional assemblies with varying subunit stoichiometries are possible. Pssm-ID: 349828 Cd Length: 178 Bit Score: 394.75 E-value: 2.25e-138
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| LGIC_ECD_nAChR_B2 | cd19025 | extracellular domain of nicotinic acetylcholine receptor subunit beta 2 (CHRNB2); This ... |
29-232 | 1.93e-128 | |||||||
extracellular domain of nicotinic acetylcholine receptor subunit beta 2 (CHRNB2); This subfamily contains the extracellular domain of nicotinic acetylcholine receptor subunit beta 2 (beta2), encoded by the CHRNB2 gene. The most abundant nicotinic subtype in the human brain is alpha4beta2 receptor which is known to assemble in two functional subunit stoichiometries, (alpha4)3(beta2)2 and (alpha4)2(beta2)3, the latter having a much higher affinity for both acetylcholine and nicotine. This subtype is implicated in the pathophysiology of neurodevelopmental disorders such as schizophrenia and autism, and neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease. Thus, pharmacological ligands targeting this subtype have been researched and developed as a treatment approach implicated in these diseases. They include agonists such as varenicline and cytisine used as smoking cessation aids, as well as positive allosteric modulators (PAMs) such as desformylflustrabromine (dFBr), which are ligands that bind to nicotinic receptors at sites other than the orthosteric site where acetylcholine binds, and are not able to act as agonists on nAChR. Pssm-ID: 349826 Cd Length: 204 Bit Score: 370.48 E-value: 1.93e-128
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| LGIC_ECD_nAChR | cd18997 | extracellular domain of nicotinic acetylcholine receptor; This family contains the ... |
54-231 | 5.12e-99 | |||||||
extracellular domain of nicotinic acetylcholine receptor; This family contains the extracellular domain of nicotinic acetylcholine receptor (nAChR), a member of the pentameric "Cys-loop" superfamily of transmitter-gated ion channels. nAChR is found in high concentrations at the nerve-muscle synapse, where it mediates fast chemical transmission of electrical signals in response to the endogenous neurotransmitter acetylcholine (ACh) released from the nerve terminal into the synaptic cleft. Thus far, seventeen nAChR subunits have been identified, including ten alpha subunits, four beta subunits, and one gamma, delta, and epsilon subunit each, all found on the cell membrane that non-selectively conducts cations (Na+, K+, Ca++). These nAChR subunits combine in several different ways to form functional nAChR subtypes which are broadly categorized as either muscle subtype located at the neuromuscular junction or neuronal subtype that are found on neurons and on other cell types throughout the body. The muscle type of nAChRs are formed by the alpha1, beta1, gamma, delta, and epsilon subunits while the neuronal type are composed of nine alpha subunits and three beta subunits, which combine in various permutations and combinations to form functional receptors. Among various subtypes of neuronal nAChRs, the homomeric alpha7 and the heteromeric alpha4beta2 receptors are the main subtypes widely distributed in the brain and implicated in the pathophysiology of neurodevelopmental disorders such as schizophrenia and autism and neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease. Among subtypes of muscle nAChRs, the heteromeric subunits (alpha1)2, beta, gamma, and delta in fetal muscle, and the gamma subunit replaced by epsilon in adult muscle have been implicated in congenital myasthenic syndromes and multiple pterygium syndromes due to various mutations. This family also includes alpha- and beta-like nAChRs found in protostomia. Pssm-ID: 349798 Cd Length: 181 Bit Score: 294.40 E-value: 5.12e-99
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| Neur_chan_LBD | pfam02931 | Neurotransmitter-gated ion-channel ligand binding domain; This family is the extracellular ... |
27-232 | 2.50e-93 | |||||||
Neurotransmitter-gated ion-channel ligand binding domain; This family is the extracellular ligand binding domain of these ion channels. This domain forms a pentameric arrangement in the known structure. Pssm-ID: 460752 [Multi-domain] Cd Length: 215 Bit Score: 281.08 E-value: 2.50e-93
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| LGIC_ECD_nAChR_proto_alpha-like | cd19031 | extracellular domain of nicotinic acetylcholine receptor subunit alpha-like found in ... |
29-234 | 1.15e-92 | |||||||
extracellular domain of nicotinic acetylcholine receptor subunit alpha-like found in protostomia; This subfamily contains the extracellular domain of nicotinic acetylcholine receptor subunit alpha-like in organisms that include arthropods, mollusks, annelid worms, and flat worms, and have their cholinergic system limited to the central nervous system. C. elegans genome encodes 29 acetylcholine receptor subunits, of which the levamisole-sensitive receptor (L-AChR) alpha-subunits, UNC-38, UNC-63, and LEV-8, included in this subfamily, form heteromers with the two non-alpha (also known as beta-like) subunits, UNC-29 and LEV-1. This receptor functions as the main excitatory postsynaptic receptor at neuromuscular junctions, indicating that many are expressed in neurons. Also included is the nicotinic alpha subunit MARA1 (Manduca ACh Receptor Alpha 1) which is expressed in Ca2+ responding neurons and contributes to the nicotinic responses in the neurons. In insects, the receptors supply fast synaptic excitatory transmission and represent a major target for several insecticides. In Drosophila, ten exclusively neuronal nAChRs have been identified, Dalpha1-Dalpha7 and Dbeta1-Dbeta3, and various combinations of these subunits and mutations are key to nAChR function. Alpha5 subunit is involved in alpha-bungarotoxin sensitivity while the alpha6 subunit is essential for the insecticidal effect of spinosad. nAChR agonists acetylcholine, nicotine, and neonicotinoids stimulate dopamine release in Drosophila larval ventral nerve cord and mutations in nAChR subunits affect how insecticides stimulate dopamine release. Pssm-ID: 349832 Cd Length: 222 Bit Score: 279.94 E-value: 1.15e-92
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| LGIC_ECD_nAChR_proto_beta-like | cd19032 | extracellular domain of nicotinic acetylcholine receptor subunit beta-like found in ... |
26-232 | 1.99e-86 | |||||||
extracellular domain of nicotinic acetylcholine receptor subunit beta-like found in protostomia; This subfamily contains the extracellular domain of nicotinic acetylcholine receptor subunit beta-like in organisms that include arthropods, mollusks, annelid worms, and flat worms, and have their cholinergic system limited to the central nervous system. C. elegans genome encodes 29 acetylcholine receptor subunits, of which the levamisole-sensitive receptor alpha-subunits (L-AChR), UNC-38, UNC-63, and LEV-8, form heteromers with the two non-alpha (also known as beta-like) subunits, UNC-29 and LEV-1 found in this subfamily. This receptor functions as the main excitatory postsynaptic receptor at neuromuscular junctions, indicating that many are expressed in neurons. In insects, the receptors supply fast synaptic excitatory transmission and represent a major target for several insecticides. In Drosophila, ten exclusively neuronal nAChR subunits have been identified, Dalpha1-Dalpha7 and Dbeta1-Dbeta3, and various combinations of these subunits and mutations are key to nAChR function. Dbeta1 subunits in dopaminergic neurons play a role in acute locomotor hyperactivity caused by nicotine in male Drosophila. Mutations of Dbeta2 or Dalpha1 nAChR subunits in Drosophila strains have significantly lower neonicotinoid-stimulated release, but no changes in nicotine-stimulated release; they are highly resistant to the neonicotinoids nitenpyram and imidacloprid. This family also includes a novel nAChR found in Aplysia bag cell neurons (neuroendocrine cells that control reproduction) which is a cholinergic ionotropic receptor that is both, nicotine insensitive and acetylcholine sensitive. Pssm-ID: 349833 [Multi-domain] Cd Length: 208 Bit Score: 263.42 E-value: 1.99e-86
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| LIC | TIGR00860 | Cation transporter family protein; The Ligand-gated Ion Channel (LIC) Family of ... |
5-419 | 4.28e-85 | |||||||
Cation transporter family protein; The Ligand-gated Ion Channel (LIC) Family of Neurotransmitter Receptors TC 1.A.9)Members of the LIC family of ionotropic neurotransmitter receptors are found only in vertebrate and invertebrate animals. They exhibit receptor specificity for (1)acetylcholine, (2) serotonin, (3) glycine, (4) glutamate and (5) g-aminobutyric acid (GABA). All of these receptor channels are probably hetero- orhomopentameric. The best characterized are the nicotinic acetyl-choline receptors which are pentameric channels of a2bgd subunit composition. All subunits arehomologous. The three dimensional structures of the protein complex in both the open and closed configurations have been solved at 0.9 nm resolution.The channel protein complexes of the LIC family preferentially transport cations or anions depending on the channel (e.g., the acetylcholine receptors are cationselective while glycine receptors are anion selective). [Transport and binding proteins, Cations and iron carrying compounds] Pssm-ID: 273305 [Multi-domain] Cd Length: 459 Bit Score: 268.51 E-value: 4.28e-85
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| LGIC_ECD_nAChR_A2 | cd19015 | extracellular domain of nicotinic acetylcholine receptor subunit alpha 2 (CHRNA2); This ... |
27-232 | 1.07e-79 | |||||||
extracellular domain of nicotinic acetylcholine receptor subunit alpha 2 (CHRNA2); This subfamily contains the extracellular domain of nicotinic acetylcholine receptor subunit alpha 2 (alpha2), encoded by the CHRNA2 gene. It is specifically expressed in medial subpallium-derived amygdalar nuclei from early developmental stages to adult. This subunit is incorporated in heteropentameric neuronal nAChRs mainly with beta2 or beta4 subunits and, along with the alpha4 and alpha7, is one of the main nAChR subunits expressed in primate brain. In Xenopus laevis oocytes, when alpha2 is co-expressed with the beta2 subunit, two subtypes of alpha2beta2 nAChR are formed with either low or high ACh sensitivity. Mouse mutation studies show that alpha2 subunits in the nAChRs influence hippocampus-dependent learning and memory as well as CA1 synaptic plasticity in adolescent mice. Pssm-ID: 349816 [Multi-domain] Cd Length: 207 Bit Score: 246.11 E-value: 1.07e-79
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| LGIC_ECD_nAChR_B1 | cd19024 | extracellular domain of nicotinic acetylcholine receptor subunit beta 1 (CHRNB1); This ... |
27-232 | 4.96e-77 | |||||||
extracellular domain of nicotinic acetylcholine receptor subunit beta 1 (CHRNB1); This subfamily contains the extracellular domain of nicotinic acetylcholine receptor subunit beta 1 (beta1), encoded by the CHRNB1 gene. It is a muscle type subunit found predominantly in the neuromuscular junction (NMJ), but also in other tissues and cell lines such as adrenal glands, carcinomas, brain, and lung. Simultaneous mRNA and protein expression of beta1 nAChR subunit is present in human placenta and skeletal muscle. The beta1 nAChR subunit forms a heteropentamer with either (alpha1)2, gamma and delta subunits in embryonic type or (alpha1)2, epsilon and delta subunits in adult type receptors. nAChRs containing beta1 subunits have been attributed to efficient clustering and anchoring of the receptors to the cytoskeleton which is important for formation of synapses in the NMJ. Mutations in the transmembrane domain region of this gene are associated with slow-channel congenital myasthenic syndrome (CMS). Pssm-ID: 349825 Cd Length: 213 Bit Score: 239.34 E-value: 4.96e-77
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| LGIC_ECD_nAChR_A3 | cd19016 | extracellular domain of nicotinic acetylcholine receptor subunit alpha 3 (CHRNA3); This ... |
27-232 | 1.16e-73 | |||||||
extracellular domain of nicotinic acetylcholine receptor subunit alpha 3 (CHRNA3); This subfamily contains the extracellular domain of nicotinic acetylcholine receptor subunit alpha 3 (alpha3), encoded by the CHRNA3 gene, and likely plays a role in neurotransmission. The alpha3 subunit is expressed in the aorta and macrophages, and may play a regulatory role in the process of vascular inflammation. One of the most broadly expressed subtype is the alpha3beta4 nAChR, also known as the ganglion-type nicotinic receptor, located in the autonomic ganglia and adrenal medulla, where activation yields post- and/or presynaptic excitation, mainly by increased Na+ and K+ permeability. The exact pentameric stochiometry of alpha3beta4 receptor is not known and functional assemblies with varying subunit stoichiometries are possible. Alpha4 plays a pivotal role in regulating the inflammatory responses in endothelial cells and macrophages, via mechanisms involving the modulations of multiple cell signaling pathways. Polymorphisms in this gene (CHRNA3) have been associated with an increased risk of smoking initiation and an increased susceptibility to lung cancer. Pssm-ID: 349817 [Multi-domain] Cd Length: 207 Bit Score: 230.59 E-value: 1.16e-73
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| LGIC_ECD_nAChR_D | cd19028 | extracellular domain of nicotinic acetylcholine receptor subunit delta (CHRND); This subfamily ... |
28-232 | 1.27e-73 | |||||||
extracellular domain of nicotinic acetylcholine receptor subunit delta (CHRND); This subfamily contains the extracellular domain of nicotinic acetylcholine receptor subunit delta (delta), encoded by the CHRND gene and found in the muscle. Delta nAChR subunit forms a heteropentamer with either (alpha1)2, beta and gamma subunits in embryonic type or (alpha1)2, beta and epsilon subunits in adult type receptors. Defects in this gene are a cause of multiple pterygium syndrome lethal type (MUPSL), congenital myasthenic syndrome slow-channel type (SCCMS), and congenital myasthenic syndrome fast-channel type (FCCMS). The slow-channel congenital myasthenic syndromes (SCCMS) are caused by prolonged opening episodes of AChR due to dominant gain-of-function mutations in the transmembrane regions of the heteropentamer. These mutations produce an increase in the channel opening rate, a decrease in the channel closing rate, or an increase in the affinity of ACh for the AChR, resulting in the stabilization of the open state or the destabilization of the closed state of the AChR. Pssm-ID: 349829 Cd Length: 221 Bit Score: 230.84 E-value: 1.27e-73
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| LGIC_ECD | cd03558 | extracellular domain (ECD) of Cys-loop neurotransmitter-gated ion channels (also known as ... |
54-231 | 6.02e-73 | |||||||
extracellular domain (ECD) of Cys-loop neurotransmitter-gated ion channels (also known as ligand-gated ion channel (LGIC)); This superfamily contains the extracellular domain (ECD) of Cys-loop neurotransmitter-gated ion channels, which include nicotinic acetylcholine receptor (nAChR), serotonin 5-hydroxytryptamine receptor (5-HT3), type-A gamma-aminobutyric acid receptor (GABAAR) and glycine receptor (GlyR). These ligand-gated ion channels (LGICs) are found across metazoans and have close homologs in bacteria. They are vital for communication throughout the nervous system. GABAAR and GlyR are anionic channels, both mediating fast inhibitory synaptic transmission. Cl- ions are selectively conducted through the GABAAR receptor pore, resulting in hyperpolarization of the neuron. nAChR is a non-selective cation channel that is permeable to Na+ and K+, and some subunit combinations are also permeable to Ca2+. Na+ enters and K+ exits to allow net flow of positively charged ions inward. 5-HT3, a cation-selective channel, binds serotonin and is permeable to Na+, K+, and Ca2+. It mediates neuronal depolarization and excitation within the central and peripheral nervous systems. These ligand-gated chloride channels are critical not only for maintaining appropriate neuronal activity, but have long been important therapeutic targets: benzodiazepines, barbiturates, some intravenous and volatile anaesthetics, alcohol, strychnine, picrotoxin, and ivermectin all derive their biological activity from acting on the inhibitory half of the Cys-loop receptor family. The ECD contains the ligand binding sites for these receptors. Pssm-ID: 349787 Cd Length: 179 Bit Score: 227.69 E-value: 6.02e-73
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| LGIC_ECD_nAChR_A5 | cd19018 | extracellular domain of nicotinic acetylcholine receptor subunit alpha 5 (CHRNA5); This ... |
26-233 | 7.16e-70 | |||||||
extracellular domain of nicotinic acetylcholine receptor subunit alpha 5 (CHRNA5); This subfamily contains the extracellular domain of nicotinic acetylcholine receptor subunit alpha 5 (alpha5), encoded by the CHRNA5 gene, which is part of the CHRNA5/A3/B4 gene cluster. Polymorphisms in this gene cluster have been identified as risk factors for nicotine dependence, lung cancer, chronic obstructive pulmonary disease, alcoholism, and peripheral arterial disease. A loss-of-function polymorphism in CHRNA5 is strongly linked to nicotine abuse and schizophrenia; the alpha5 nAChR subunit is strategically situated in the prefrontal cortex (PFC), where a loss-of-function in this subunit may contribute to cognitive disruptions in both disorders. Alpha5 forms heteropentamers with alpha3beta2 or alpha3beta4 nAChRs which increases the calcium permeability of the resulting receptors possibly playing significant roles in the initiation of ACh-induced signaling cascades under normal and pathological condition. Acetylcholine (ACh) release and signaling via alpha4/beta2 nAChR subunits plays a central role in the control of attention, but a subset of these oligomers also contains alpha5 subunit. A strong association is seen between a CHRNA5 polymorphism and the risk of lung cancer, especially in smokers. Pssm-ID: 349819 [Multi-domain] Cd Length: 207 Bit Score: 220.99 E-value: 7.16e-70
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| LGIC_ECD_nAChR_proto-like | cd19033 | nicotinic acetylcholine receptor (nAChR) subunit extracellular domain in molluscs and annelids; ... |
54-231 | 2.92e-69 | |||||||
nicotinic acetylcholine receptor (nAChR) subunit extracellular domain in molluscs and annelids; This subfamily contains the extracellular domain of nicotinic acetylcholine receptor subunit found in molluscs, including several Lymnaea nAChRs, and annelids that are mostly uncharacterized. To date, 12 Lymnaea nAChRs have been identified which can be subdivided in two subtypes according to the residues that may be contributing to the selectivity of ion conductance. Phylogenetic analysis of the nAChR gene sequences suggests that anionic nAChRs in molluscs probably evolved from cationic ancestors through amino acid substitutions in the ion channel pore which is a mechanism different from acetylcholine-gated channels in other invertebrates. Pssm-ID: 349834 Cd Length: 183 Bit Score: 218.31 E-value: 2.92e-69
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| LGIC_ECD_nAChR_B3 | cd19026 | extracellular domain of nicotinic acetylcholine receptor subunit beta 3 (CHRNB3); This ... |
54-230 | 4.01e-69 | |||||||
extracellular domain of nicotinic acetylcholine receptor subunit beta 3 (CHRNB3); This subfamily contains the extracellular domain of nicotinic acetylcholine receptor subunit beta 3 (beta3), encoded by the CHRNB3 gene. CHRNB3 polymorphisms have been reported to potentially affect nicotine-induced upregulation of nicotinic and to be associated with disorders such as schizophrenia, autism, and cancer. Beta3 subunit is depleted in the striatum of Parkinson's disease patients. Rare variants in CHRNB3 are also implicated in risk for alcohol and cocaine dependence and independently associated with bipolar disorder. Human alpha6beta2beta3* (* indicating possible additional assembly partners) nAChRs on dopaminergic neurons are important targets for drugs to treat nicotine addiction and Parkinson's disease; (alpha6beta2)(alpha4beta2)beta3 nAChR is essential for addiction to nicotine and a target for drug development for smoking cessation. Pssm-ID: 349827 Cd Length: 179 Bit Score: 217.92 E-value: 4.01e-69
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| LGIC_ECD_nAChR_G | cd19029 | extracellular domain of nicotinic acetylcholine receptor subunit gamma (CHRNG); This subfamily ... |
52-232 | 1.83e-67 | |||||||
extracellular domain of nicotinic acetylcholine receptor subunit gamma (CHRNG); This subfamily contains the extracellular domain of nicotinic acetylcholine receptor subunit gamma (gamma), encoded by the CHRNG gene expressed during early fetal development, and replaced by the epsilon subunit in the adult. The gamma subunit forms a heteropentamer with (alpha1)2, beta, and delta and plays a role in neuromuscular organogenesis and ligand binding. Disruption of gamma subunit expression prevents the correct localization of the receptor in cell membranes. Mutations in CHRNG may cause the non-lethal Escobar variant (EVMPS) and lethal form (LMPS) of multiple pterygium syndrome (MPS), a condition characterized by prenatal growth failure with pterygium and akinesia leading to muscle weakness and severe congenital contractures, as well as scoliosis. Muscle-type acetylcholine receptor is the major antigen in the autoimmune disease myasthenia gravis. Pssm-ID: 349830 Cd Length: 193 Bit Score: 213.86 E-value: 1.83e-67
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| Neur_chan_memb | pfam02932 | Neurotransmitter-gated ion-channel transmembrane region; This family includes the four ... |
239-447 | 3.36e-65 | |||||||
Neurotransmitter-gated ion-channel transmembrane region; This family includes the four transmembrane helices that form the ion channel. Pssm-ID: 460753 [Multi-domain] Cd Length: 232 Bit Score: 209.43 E-value: 3.36e-65
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| LGIC_ECD_cation | cd18989 | extracellular domain (LBD) of cationic Cys-loop neurotransmitter-gated ion channels; This ... |
54-231 | 1.77e-64 | |||||||
extracellular domain (LBD) of cationic Cys-loop neurotransmitter-gated ion channels; This superfamily contains the extracellular domain (ECD) of cationic Cys-loop neurotransmitter-gated ion channels, which include nicotinic acetylcholine receptor (nAChR), serotonin 5-hydroxytryptamine receptor (5-HT3), and zinc-activated ligand-gated ion channel (ZAC) receptor. These ligand-gated ion channels (LGICs) are found across metazoans and have close homologs in bacteria. They are vital for communication throughout the nervous system. nAChR is a non-selective cation channel that is permeable to Na+ and K+, and some subunit combinations are also permeable to Ca2+. Na+ enters and K+ exits to allow net flow of positively charged ions inward. 5-HT3, a cation-selective channel, binds serotonin and is permeable to Na+, K+, and Ca2+. It mediates neuronal depolarization and excitation within the central and peripheral nervous systems. ZAC forms an ion channel gated by Zn2+, Cu2+, and H+ and is non-selectively permeable to monovalent cations. However, the role of ZAC in Zn2+, Cu2+, and H+ signaling require is as yet unknown. Pssm-ID: 349790 [Multi-domain] Cd Length: 180 Bit Score: 205.67 E-value: 1.77e-64
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| LGIC_ECD_nAChR_A9 | cd19022 | extracellular domain of neuronal acetylcholine receptor subunit alpha 9 (CHRNA9); This ... |
28-231 | 2.08e-60 | |||||||
extracellular domain of neuronal acetylcholine receptor subunit alpha 9 (CHRNA9); This subfamily contains the extracellular domain of nicotinic acetylcholine receptor subunit alpha 9 (alpha9), encoded by the CHRNA9 gene. This protein is involved in cochlea hair cell development and is also expressed in the outer hair cells (OHCs) of the adult cochlea as well as in keratinocytes, the pituitary gland, B-cells, and T-cells. Mammalian alpha9 subunits can form functional homomeric alpha9 receptors as well as the heteromeric alpha9alpha10 receptors, the latter being atypical since the heteromeric alpha9alpha10 receptor is composed only of alpha subunits compared to nAChRs typically assembled from alpha and beta subunits. A stoichiometry of (alpha9)2(alpha10)3 has been determined for the rat recombinant receptor. The alpha9alpha10 nAChR is an important therapeutic target for pain; selective block of alpha9alpha10 nicotinic acetylcholine receptors by the conotoxin RgIA has been shown to be analgesic in an animal model of nerve injury pain, and accelerates recovery of nerve function after injury, possibly through immune/inflammatory-mediated mechanisms. CHRNA9 polymorphisms are associated with non-small cell lung cancer, and effect of a particular SNP (rs73229797) and passive smoking exposure on risk of breast malignancy has been observed. Pssm-ID: 349823 Cd Length: 207 Bit Score: 196.42 E-value: 2.08e-60
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| LGIC_ECD_nAChR_A1 | cd19014 | extracellular domain of nicotinic acetylcholine receptor subunit alpha 1 (CHRNA1); This ... |
27-232 | 2.52e-60 | |||||||
extracellular domain of nicotinic acetylcholine receptor subunit alpha 1 (CHRNA1); This subfamily contains the extracellular domain of nicotinic acetylcholine receptor subunit alpha 1 (alpha1), encoded by the CHRNA1 gene. These muscle type nicotinic subunits form heteropentamers with other nAChR subunits, most broadly expressed as combination of two alpha1, beta1, delta, and epsilon subunits in mature muscles, and of two alpha1, beta1, delta, and gamma in embryonic cells. The alpha1 subunit in human nAChR is the primary target of Myasthenia gravis antibodies that disrupt communication between the nervous system and the muscle, causing chronic muscle weakness. Pssm-ID: 349815 Cd Length: 210 Bit Score: 196.23 E-value: 2.52e-60
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| LGIC_ECD_nAChR_A4 | cd19017 | extracellular domain of neuronal acetylcholine receptor subunit alpha 4 (CHRNA4); This ... |
54-230 | 5.63e-60 | |||||||
extracellular domain of neuronal acetylcholine receptor subunit alpha 4 (CHRNA4); This subfamily contains the extracellular domain of nicotinic acetylcholine receptor subunit alpha 4 (alpha4), encoded by the CHRNA4 gene. Alpha4 forms a functional nAChR by interacting with either nAChR beta2 or beta4 subunits. Alpha4beta2, the major heteropentameric nAChR in the brain, exists in two isoforms, (alpha4)3(beta2)2 and (alpha4)2(beta2)3, with the latter believed to constitute the majority of alpha4beta2 nAChR in the cortex. Both isoforms contain two canonical alpha4:beta2 ACh-binding sites with either low or high ACh sensitivity. This protein is an integral membrane receptor subunit that can interact with either nAChR beta-2 or nAChR beta-4 to form a functional receptor. Mutations in this gene (CHRNA4) cause nocturnal frontal lobe epilepsy type 1. Polymorphisms in this gene may provide protection against nicotine addiction. Pssm-ID: 349818 Cd Length: 181 Bit Score: 194.11 E-value: 5.63e-60
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| LGIC_ECD_nAChR_A6 | cd19019 | extracellular domain of nicotinic acetylcholine receptor subunit alpha 6 (CHRNA6); This ... |
54-230 | 1.37e-59 | |||||||
extracellular domain of nicotinic acetylcholine receptor subunit alpha 6 (CHRNA6); This subfamily contains the extracellular domain of nicotinic acetylcholine receptor subunit alpha 6 (alpha6), encoded by the CHRNA6 gene. Human (alpha6beta2)(alpha4beta2)3 nicotinic acetylcholine receptors (AChRs) are essential for addiction to nicotine and a target for drug development for smoking cessation. In xenopus oocytes, data show efficient expression of (alpha6beta2)2beta3 AChR subunits with only small changes in alpha6 subunits, while not altering AChR pharmacology or channel structure. Alternatively spliced transcript variants have been observed for this gene. Single nucleotide polymorphisms in this gene have been associated with both nicotine and alcohol dependence. CHRNA6 has a cellular expression signature for retinal ganglion cells with high correlation to Thy1, a known marker, and is preferentially expressed by retinal ganglion cells (RGCs) in the young and adult mouse retina and expression is reduced in glaucoma. A genetic variant in CHRNB3#CHRNA6 cluster is associated with esophageal adenocarcinoma. Pssm-ID: 349820 [Multi-domain] Cd Length: 181 Bit Score: 193.32 E-value: 1.37e-59
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| LGIC_ECD_nAChR_A10 | cd19023 | extracellular domain of neuronal acetylcholine receptor subunit alpha 10 (CHRNA10); This ... |
54-231 | 2.03e-58 | |||||||
extracellular domain of neuronal acetylcholine receptor subunit alpha 10 (CHRNA10); This subfamily contains the extracellular domain of nicotinic acetylcholine receptor subunit alpha 10 (alpha10), encoded by the CHRNA10 gene. This protein is involved in cochlea hair cell development and is also expressed in the outer hair cells (OHCs) of the adult cochlea as well as in keratinocytes, the pituitary gland, B-cells, and T-cells. Unlike alpha9 nAChR subunits, alpha10 subunits do not generate functional channels when expressed heterologously, suggesting that alpha10 might serve as a structural subunit, much like a beta subunit of heteromeric receptors, providing only complementary components to the agonist binding site. Mammalian alpha10 subunits can form functional heteromeric alpha9alpha10 receptors, an atypical heteromeric receptor since it is composed only of alpha subunits compared to nAChRs typically assembled from alpha and beta subunits. A stoichiometry of (alpha9)2(alpha10)3 has been determined for the rat recombinant receptor. The alpha9alpha10 nAChR is an important therapeutic target for pain; selective block of alpha9alpha10 nicotinic acetylcholine receptors by the conotoxin RgIA has been shown to be analgesic in an animal model of nerve injury pain, and accelerates recovery of nerve function after injury, possibly through immune/inflammatory-mediated mechanisms. Pssm-ID: 349824 Cd Length: 181 Bit Score: 190.20 E-value: 2.03e-58
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| LGIC_ECD_nAChR_E | cd19030 | extracellular domain of nicotinic acetylcholine receptor subunit epsilon (CHRNE); This ... |
54-231 | 5.99e-58 | |||||||
extracellular domain of nicotinic acetylcholine receptor subunit epsilon (CHRNE); This subfamily contains the extracellular domain of nicotinic acetylcholine receptor subunit epsilon (epsilon), encoded by the CHRNE gene and found in adult skeletal muscle. Epsilon subunit forms a heteropentamer with (alpha1)2, beta and delta after birth, replacing the gamma subunit seen in embryonic receptors. The adult-type epsilon-AChR has a higher conductance and a shorter open time compared to embryonic gamma-AChR and the open channel is non-selectively cation permeable. Mutations of the CHRNE gene are the most common causes of congenital myasthenic syndrome (CMS), most of which are autosomal recessive loss-of-function mutations, resulting in endplate AChR deficiency. A highly fatal fast-channel syndrome is caused by AChR epsilon subunit mutation (Trp to Arg; changing environment from anionic to cationic) at the agonist binding site at the alpha/epsilon interface of the receptor, thus disrupting agonist binding affinity and gating efficiency. Pssm-ID: 349831 Cd Length: 191 Bit Score: 189.45 E-value: 5.99e-58
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| LGIC_ECD_nAChR_A7 | cd19020 | extracellular domain of neuronal acetylcholine receptor subunit alpha 7 (CHRNA7); This ... |
54-231 | 9.33e-58 | |||||||
extracellular domain of neuronal acetylcholine receptor subunit alpha 7 (CHRNA7); This subfamily contains the extracellular domain of nicotinic acetylcholine receptor subunit alpha 7 (alpha7), encoded by the CHRNA7 gene. Alpha7 subunits form a homo-pentameric channel, displays marked permeability to calcium ions and is a major component of brain nicotinic receptors that are blocked by, and highly sensitive to, alpha-bungarotoxin. This protein is ubiquitously expressed in both the central nervous system and in the periphery, in several tissues, including adrenal, small intestine, testis, and stomach. CHRNA7 is located in a region identified as a major susceptibility locus for juvenile myoclonic epilepsy and a chromosomal location involved in the genetic transmission of schizophrenia. It is also genetically linked to other disorders with cognitive deficits, including bipolar disorder, ADHD, Alzheimer's disease, and Rett syndrome. An evolutionarily recent partial duplication of CHRNA7 on chromosome 15 forms a new gene, CHRFAM7A or FAM7A, which encodes the protein dup-alpha7. This protein assembles with alpha7 subunits, results in fewer binding sites and is a dominant negative regulator of alpha7 nAChR function. Pssm-ID: 349821 [Multi-domain] Cd Length: 180 Bit Score: 188.66 E-value: 9.33e-58
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| LGIC_ECD_nAChR_A7L | cd19021 | extracellular domain of neuronal acetylcholine receptor subunit alpha-7-like; This family ... |
56-231 | 2.91e-48 | |||||||
extracellular domain of neuronal acetylcholine receptor subunit alpha-7-like; This family contains the extracellular domain of nicotinic acetylcholine receptor (nAChR), a member of the pentameric "Cys-loop" superfamily of transmitter-gated ion channels. nAChR is found in high concentrations at the nerve-muscle synapse, where it mediates fast chemical transmission of electrical signals in response to the endogenous neurotransmitter acetylcholine (ACh) released from the nerve terminal into the synaptic cleft. Thus far, seventeen nAChR subunits have been identified, including ten alpha subunits, four beta subunits and one gamma, delta, and epsilon subunit each, all found on the cell membrane that non-selectively conducts cations (Na+, K+, Ca++). These nAChR subunits combine in several different ways to form functional nAChR subtypes which are broadly categorized as either muscle subtype located at the neuromuscular junction or neuronal subtype that are found on neurons and on other cell types throughout the body. The muscle type of nAChRs are formed by the alpha1, beta1, gamma, delta, and epsilon subunits while the neuronal type are composed of nine alpha subunits and three beta subunits, which combine in various permutations and combinations to form functional receptors. Among various subtypes of neuronal nAChRs, the homomeric alpha7 and the heteromeric alpha4beta2 receptors are the main subtypes widely distributed in the brain and implicated in the pathophysiology of neurodevelopmental disorders such as schizophrenia and autism and neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease. Pssm-ID: 349822 [Multi-domain] Cd Length: 179 Bit Score: 163.67 E-value: 2.91e-48
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| LGIC_TM_nAChR | cd19064 | transmembrane domain of nicotinic acetylcholine receptor (nAChR); This family contains ... |
233-322 | 1.92e-45 | |||||||
transmembrane domain of nicotinic acetylcholine receptor (nAChR); This family contains transmembrane (TM) domain of the nicotinic acetylcholine receptor (nAChR). The transmembrane region consists of four transmembrane-spanning alpha-helical segments (M1-M4) that are linked by loops. The intracellular loop that links M1 and M2 determines the ion selectivity of the channel. nAChR is found in high concentrations at the nerve-muscle synapse, where it mediates fast chemical transmission of electrical signals in response to the endogenous neurotransmitter acetylcholine (ACh) released from the nerve terminal into the synaptic cleft. Thus far, seventeen nAChR subunits have been identified, including ten alpha subunits, four beta subunits and one gamma, delta, and epsilon subunit each, all found on the cell membrane that non-selectively conducts cations (Na+, K+, Ca++). These nAChR subunits combine in several different ways to form functional nAChR subtypes which are broadly categorized as either muscle subtype located at the neuromuscular junction or neuronal subtype that are found on neurons and on other cell types throughout the body. The muscle type of nAChRs are formed by the alpha1, beta1, gamma, delta, and epsilon subunits while the neuronal type are composed of nine alpha subunits and three beta subunits, which combine in various permutations and combinations to form functional receptors. Among various subtypes of neuronal nAChRs, the homomeric alpha7 and the heteromeric alpha4beta2 receptors are the main subtypes widely distributed in the brain and implicated in the pathophysiology of neurodevelopmental disorders such as schizophrenia and autism and neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease. Among subtypes of muscle nAChRs, the heteromeric subunits (alpha1)2, beta, gamma, and delta in fetal muscle, and the gamma subunit replaced by epsilon in adult muscle have been implicated in congenital myasthenic syndromes and multiple pterygium syndromes due to various mutations. This family also includes alpha- and beta-like nAChRs found in protostomia. Pssm-ID: 349866 [Multi-domain] Cd Length: 113 Bit Score: 153.82 E-value: 1.92e-45
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| LGIC_AChBP | cd18995 | acetylcholine binding protein (AChBP); This family contains acetylcholine binding protein ... |
54-231 | 5.43e-37 | |||||||
acetylcholine binding protein (AChBP); This family contains acetylcholine binding protein (AChBP) which is a soluble extracellular domain homolog secreted by protostomia, and has been widely recognized as a surrogate for the ligand binding domain of nicotinic acetylcholine receptors (nAChRs). AChBP forms a pentameric structure where the interfaces between the subunits provide an acetylcholine (ACh) binding pocket homologous to the binding pocket of nAChRs. Thus far, AChBPs have been characterized only in aquatic mollusks, which have shown low sensitivity to neonicotinoids, the insecticides targeting insect nAChRs. Lymnaea stagnalis acetylcholine binding protein (Ls-AChBP) which has been found in glial cells as a water-soluble protein modulating synaptic ACh concentration has its the binding pocket show better resemblance as it contains all the five aromatic residues fully conserved in nAChR. Five AChBP subunits have been characterized in Pardosa pseudoannulata, a predator enemy against rice insect pests, and share higher sequence similarities with nAChR subunits of both insects and mammals compared with mollusk AChBP subunits. Pssm-ID: 349796 Cd Length: 180 Bit Score: 133.64 E-value: 5.43e-37
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| LGIC_ECD_5-HT3B | cd19012 | extracellular domain of serotonin 5-hydroxytryptamine receptor (5-HT3) receptor subunit B ... |
38-231 | 1.99e-32 | |||||||
extracellular domain of serotonin 5-hydroxytryptamine receptor (5-HT3) receptor subunit B (5HT3B); This subfamily contains extracellular domain of subunit B of serotonin 5-HT3 receptor (5-HT3BR), encoded by the HTR3B gene. 5-HT3B is not functional as a homopentameric complex and is co-expression with the 5-HT3A subunit, resulting in heteromeric 5-HT3AB receptors that are functionally distinct from homomeric 5-HT3A receptors. This receptor causes fast, depolarizing responses in neurons after activation, with affinities of competitive ligands at the two receptor subtypes extracellular domains mostly similar. HTR3B gene variants may contribute to variability in severity of and response to anti-emetic therapy for nausea and vomiting in pregnancy, as well as efficacy of ondansetron in cancer chemotherapy, radiation therapy, or surgery. 5-HT3B subunit affects high-potency inhibition of 5-HT3 receptors by morphine by reducing its affinity at its high-affinity, non-competitive site. Pssm-ID: 349813 Cd Length: 210 Bit Score: 122.71 E-value: 1.99e-32
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| LGIC_ECD_5-HT3 | cd18996 | extracellular domain of serotonin 5-HT3 receptor; This family contains extracellular domain of ... |
20-231 | 5.47e-32 | |||||||
extracellular domain of serotonin 5-HT3 receptor; This family contains extracellular domain of serotonin 5-HT3 receptor which belongs to the Cys-loop superfamily of ligand-gated ion channels (LGICs). This ion channel is cation-selective and mediates neuronal depolarization and excitation within the central and peripheral nervous systems. Like other ligand gated ion channels, the 5-HT3 receptor consists of five subunits arranged around a central ion conducting pore, which is permeable to Na+, K+, and Ca2+ ions. Binding of the neurotransmitter 5-hydroxytryptamine (serotonin) to the 5-HT3 receptor opens the channel, which then leads to an excitatory response in neurons, and the rapidly activating, desensitizing, inward current is predominantly carried by Na+ and K+ ions. This receptor is most closely related by homology to the nicotinic acetylcholine receptor (nAChR). Five subunits have been identified for this family: 5-HT3A, 5-HT3B, 5-HT3C, 5-HT3D, and 5-HT3E, encoded by HTR3A-E genes. Only 5-HT3A subunits are able to form functional homomeric receptors, whereas the 5-HT3B, C, D, and E subunits form heteromeric receptors with 5-HT3A. Different receptor subtypes are important mediators of nausea and vomiting during chemotherapy, pregnancy, and following surgery, while some contribute to neuro-gastroenterologic disorders such irritable bowel syndrome (IBS) and eating disorders as well as co-morbid psychiatric conditions. 5-HT3 receptor antagonists are established treatments for emesis and IBS, and are beneficial in the treatment of psychiatric diseases. Pssm-ID: 349797 Cd Length: 215 Bit Score: 121.33 E-value: 5.47e-32
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| LGIC_TM_cation | cd19051 | transmembrane domain of Cys-loop neurotransmitter-gated ion channels, includes 5HT3, nAChR, ... |
233-322 | 3.86e-30 | |||||||
transmembrane domain of Cys-loop neurotransmitter-gated ion channels, includes 5HT3, nAChR, and ZAC; This superfamily contains the transmembrane (TM) domain of cationic Cys-loop neurotransmitter-gated ion channels, which include nicotinic acetylcholine receptor (nAChR), serotonin 5-hydroxytryptamine receptor (5-HT3), and zinc-activated ligand-gated ion channel (ZAC) receptor. The transmembrane region consists of four transmembrane-spanning alpha-helical segments (M1-M4) that are linked by loops. The intracellular loop that links M1 and M2 determines the ion selectivity of the channel. The ligand-gated ion channels (LGICs) in this family are found across metazoans and have close homologs in bacteria. They are vital for communication throughout the nervous system. nAChR is a non-selective cation channel that is permeable to Na+ and K+, and some subunit combinations are also permeable to Ca2+. Na+ enters and K+ exits to allow net flow of positively charged ions inward. 5-HT3, a cation-selective channel, binds serotonin and is permeable to Na+, K+, and Ca2+. It mediates neuronal depolarization and excitation within the central and peripheral nervous systems. ZAC forms an ion channel gated by Zn2+, Cu2+, and H+ and is non-selectively permeable to monovalent cations. However, the role of ZAC in Zn2+, Cu2+, and H+ signaling require is as yet unknown. Pssm-ID: 349853 [Multi-domain] Cd Length: 112 Bit Score: 112.84 E-value: 3.86e-30
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| LGIC_ECD_5-HT3C_E | cd19013 | extracellular domain of serotonin 5-hydroxytryptamine receptor (5-HT3) receptor subunit E ... |
44-231 | 8.29e-30 | |||||||
extracellular domain of serotonin 5-hydroxytryptamine receptor (5-HT3) receptor subunit E (5HT3E); may include subunits C and D (5-HT3C,D); This subfamily contains extracellular domain of subunit E of serotonin 5-HT3 receptor (5-HT3ER), encoded by the HTR3E gene, and may also contain subunits C and D, all three encoding genes forming a cluster on chromosome 3. Data show that 5-HT3C, 5-HT3D, and 5-HT3E subunits are co-expressed with 5-HT3A in cell bodies of myenteric neurons, and that 5-HT3A and 5-HT3D are expressed in submucosal plexus of the human large intestine while HTR3E is restricted to the colon, intestine, and stomach. None of these subunits can form functional homopentamers, but, upon co-expression with the 5-HT3A subunit, they give rise to functional receptors that differ in maximal responses to 5-HT, and thus modulate 5-HT3 receptor's pharmacological profile. HTR3A and HTR3E polymorphisms have been shown to remarkably up-regulate the expression of 5-HT3 receptors, which have been proved to cause the gastric functional disorders including emesis, eating disorders and IBS-D. Pssm-ID: 349814 Cd Length: 215 Bit Score: 115.57 E-value: 8.29e-30
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| LGIC_ECD_5-HT3A | cd19011 | extracellular domain of serotonin 5-hydroxytryptamine receptor (5-HT3) receptor subunit A ... |
29-231 | 1.54e-27 | |||||||
extracellular domain of serotonin 5-hydroxytryptamine receptor (5-HT3) receptor subunit A (5HT3A); This subfamily contains extracellular domain of subunit A of serotonin 5-HT3 receptor (5-HT3AR), encoded by the HTR3A gene. 5-HT3A subunit forms a homopentameric complex or a heterologous combination with other subunits (B-E). Heteromeric combination of A and B subunits provides the full functional features of this receptor, since either subunit alone results in receptors with very low conductance and response amplitude. 5-HT3A receptors are located in the dorsal vagal complex of the brainstem and in the gastrointestinal (GI) tract, and form a channel circuit that controls gut motility, secretion, visceral perception, and the emesis reflex. These receptors are implicated in several GI and psychiatric disorder conditions including anxiety, depression, bipolar disorder, and irritable bowel syndrome (IBS). Several 5-HT3AR antagonists, such as the isoquinoline Palonosetron, are in clinical use to control emetic reflexes associated with gastrointestinal pathologies and cancer therapies. SNPs in the 5-HT3A serotonin receptor gene are associated with psychiatric disorders. Pssm-ID: 349812 Cd Length: 208 Bit Score: 109.16 E-value: 1.54e-27
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| LGIC_ECD_GABAAR_A2 | cd19035 | extracellular domain of gamma-aminobutyric acid receptor subunit alpha-2 (GABAAR-A2 or GABRA2); ... |
40-231 | 1.04e-15 | |||||||
extracellular domain of gamma-aminobutyric acid receptor subunit alpha-2 (GABAAR-A2 or GABRA2); This family contains extracellular domain of gamma-aminobutyric acid receptor subunit alpha-2 (GABAAR-A2), a protein that is encoded by the GABRA2 gene in humans. GABAAR is an anionic channel, mediating fast inhibitory synaptic transmission. Upon gamma-aminobutyric acid (GABA) binding to the ligand binding site on the ECD, Cl- ions are selectively conducted through the GABAAR pore, resulting in hyperpolarization of the neuron. GABAAR is the principal mediator of rapid inhibitory synaptic transmission in the human brain. A decline in GABAAR signaling triggers hyperactive neurological disorders such as insomnia, anxiety, and epilepsy. The alpha-2 subunit forms heteropentamers with other GABAAR subunits, most broadly expressed as combination of alpha2beta3gamma2. The alpha-2 (GABRA2) subunit is found primarily in the forebrain and hippocampus, and is more confined to areas of the brain compared to other alpha subunits. GABRA2 increases the risk of anxiety, making it a target for treating behavioral disorders including alcohol dependence, and drug use. GABRA2 is a binding site for benzodiazepines (psychoactive drugs known to reduce anxiety), causing chloride channels to open, leading to the hyper-polarization of the membrane. Other anxiolytic drugs such as Diazepam bind this subunit to induce inhibitory effects. GABRA2 is associated with reward behavior when it activates the insula, the part of the cerebral cortex responsible for emotions. GABA alpha2 and/or alpha3 receptor subtypes are also involved in GABAergic modulation of prolactin secretion. Pssm-ID: 349836 [Multi-domain] Cd Length: 203 Bit Score: 75.45 E-value: 1.04e-15
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| LGIC_ECD_GABAAR_pi | cd19004 | extracellular domain of gamma-aminobutyric acid receptor subunit pi (GABRP); This family ... |
54-181 | 8.39e-15 | |||||||
extracellular domain of gamma-aminobutyric acid receptor subunit pi (GABRP); This family contains extracellular domain of pi subunit of type-A gamma-aminobutyric acid receptor (GABAAR). GABAAR is an anionic channel, mediating fast inhibitory synaptic transmission. Upon gamma-aminobutyric acid (GABA) binding to the ligand binding site on ECD, Cl- ions are selectively conducted through the GABAAR pore, resulting in hyperpolarization of the neuron. GABAAR is the principal mediator of rapid inhibitory synaptic transmission in the human brain. A decline in GABAAR signaling triggers hyperactive neurological disorders such as insomnia, anxiety, and epilepsy. GABRP is expressed mainly in non-neuronal tissues such as the mammary gland, prostate gland, lung, thymus, and uterus. It is also highly expressed in certain types of cancer such as basal-like breast cancer and pancreatic ductal adenocarcinoma. GABRP is involved in inhibitory synaptic transmission in the central nervous system. Its assembly with other GABAAR subunits alters the sensitivity of recombinant receptors to modulatory agents such as pregnanolone. Studies suggest that polymorphisms in the GABRP gene may be associated with the susceptibility to systematic lupus erythematosus (SLE). Pssm-ID: 349805 Cd Length: 182 Bit Score: 72.32 E-value: 8.39e-15
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| LGIC_ECD_anion | cd18987 | extracellular domain (ECD) of anionic Cys-loop neurotransmitter-gated ion channels; This ... |
54-186 | 2.59e-14 | |||||||
extracellular domain (ECD) of anionic Cys-loop neurotransmitter-gated ion channels; This family contains the extracellular domain (ECD) of anionic Cys-loop neurotransmitter-gated ion channels which include type-A gamma-aminobutyric acid receptor (GABAAR), glycine receptor (GlyR), invertebrate glutamate-gated chloride channel (GluCl), and histimine-gated chloride channel (HisCl). These neurotransmitter receptors directly mediate chloride permeability and constitute one half of the Cys-loop receptor family. Receptors in this family are composed of five either identical or homologous subunits, which generate diversity in functional profiles and pharmacological preferences. GABAAR and GlyR, both mediate fast inhibitory synaptic transmission. Cl- ions are selectively conducted through the GABAAR receptor pore, resulting in hyperpolarization of the neuron. GluCl channels are found only in protostomia, but are closely related to mammalian glycine receptors (GlyRs). They have several roles in these invertebrates, including controlling locomotion and feeding, and mediating sensory inputs into behavior. Ligand-gated chloride channels are critical not only for maintaining appropriate neuronal activity, but have long been important therapeutic targets: benzodiazepines, barbiturates, some intravenous and volatile anaesthetics, alcohol, strychnine, picrotoxin, and ivermectin all derive their biological activity from acting on this inhibitory half of the Cys-loop receptor family. Many of the therapeutically useful compounds acting at Cys-loop receptors target an allosteric site. The sites in Cys-loop receptors at which these allosteric ligands bind and their structure-based mechanisms of action are largely unresolved. Pssm-ID: 349788 [Multi-domain] Cd Length: 185 Bit Score: 71.17 E-value: 2.59e-14
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| LGIC_ECD_GABAAR_A3 | cd19036 | extracellular domain of gamma-aminobutyric acid receptor subunit alpha-3 (GABAAR-A3 or GABRA3); ... |
40-231 | 6.96e-13 | |||||||
extracellular domain of gamma-aminobutyric acid receptor subunit alpha-3 (GABAAR-A3 or GABRA3); This family contains extracellular domain of gamma-aminobutyric acid receptor subunit alpha-3 (GABAAR-A3), a protein that is encoded by the GABRA3 gene in humans. GABAAR is an anionic channel, mediating fast inhibitory synaptic transmission. Upon gamma-aminobutyric acid (GABA) binding to the ligand binding site on the ECD, Cl- ions are selectively conducted through the GABAAR pore, resulting in hyperpolarization of the neuron. GABAAR is the principal mediator of rapid inhibitory synaptic transmission in the human brain. A decline in GABAAR signaling triggers hyperactive neurological disorders such as insomnia, anxiety, and epilepsy. The alpha-3 subunit forms heteropentamers with other GABAAR subunits, most broadly expressed as combination of alpha3betagamma2, typically found post-synaptically. Rare loss-of-function variants in GABRA3 have been shown to increase the risk for a varying combination of epilepsy, intellectual disability/developmental delay, and dysmorphic features. GABRA3, normally exclusively expressed in adult brain, is also expressed in breast cancer, with high expression being inversely correlated with breast cancer survival. It activates the AKT pathway to promote breast cancer cell migration, invasion, and metastasis. GABRA3 promotes lymphatic metastasis in lung adenocarcinoma by mediating upregulation of matrix metalloproteinases, MMP-2 and MMP-9, through activation of the JNK/AP-1 signaling pathway. GABRA3 is overexpressed in human hepatocellular carcinoma growth and, with GABA, promotes the proliferation of cancer cells. Pssm-ID: 349837 Cd Length: 200 Bit Score: 67.36 E-value: 6.96e-13
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| LGIC_ECD_GluCl | cd18993 | glutamate-gated chloride channel (GluCl) extracellular domain; This subfamily contains ... |
81-186 | 4.06e-12 | |||||||
glutamate-gated chloride channel (GluCl) extracellular domain; This subfamily contains extracellular domain of glutamate-gated chloride channel (GluCl) found only in protostomia, but are closely related to mammalian glycine receptors. They have several roles in these invertebrates, including controlling locomotion and feeding, and mediating sensory inputs into behavior. Comparison of the GluCl gene families between organisms shows that insect gene family is relatively simple, while that found in nematodes tends to be larger and more diverse. Glutamate is an inhibitory neurotransmitter that shapes the responses of projection neurons to olfactory stimuli in the Drosophila. GluCls are targeted by the macrocyclic lactone family of anthelmintics and pesticides in arthropods and nematodes, thus making the GluCls of considerable medical and economic importance. In Drosophila melanogaster, GluCl mediates sensitivity to the antiparasitic agents ivermectin and nodulisporic acid, suggesting that their drug target is the same throughout the Ecdysozoa. Pssm-ID: 349794 Cd Length: 183 Bit Score: 64.54 E-value: 4.06e-12
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| LGIC_ECD_GABAR_RDL-like | cd19008 | gamma-aminobutyric acid receptor subunit beta-like extracellular domain in protostomia, such ... |
67-181 | 6.42e-12 | |||||||
gamma-aminobutyric acid receptor subunit beta-like extracellular domain in protostomia, such as RDL (resistant to dieldrin); This family contains extracellular domain of beta-like subunits of type-A gamma-aminobutyric acid receptor (GABAAR) found in protostomia, similar to Drosophila melanogaster resistant to dieldrin (RDL) subunits. Drosophila melanogaster expresses three GABA-receptor subunit orthologs: (RDL, resistant to dieldrin; GRD, GABA/glycine-like receptor of Drosophila; LCCH3, ligand-gated chloride channel homolog 3), and may possibly form homo- and/or heteropentameric associations. GABAARs are known to be the molecular targets of a class of insecticides. The resulting pentameric receptors in this family have been shown to be activated by insect GABA-receptor agonists muscimol and CACA, and blocked by antagonists fipronil, dieldrin, and picrotoxin, but not bicuculline. GABAARs are abundant in the CNS, where their physiological role is to mediate fast inhibitory neurotransmission. In insects, this inhibitory transmission plays a crucial role in olfactory information processing. Bombyx mori includes three RDL (RD1, RD2, RD3), one LCCH3, and one GRD subunits. Its RDL1 gene has RNA-editing sites, and the RDL1 and RDL3 genes possess alternative splicing, enhancing the diversity of its GABA-receptor gene family. The three RDL subunits may have arisen from two duplication events. Pssm-ID: 349809 Cd Length: 184 Bit Score: 64.01 E-value: 6.42e-12
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| LGIC_ECD_GABAAR | cd18990 | gamma-aminobutyric acid receptor extracellular domain; This family contains extracellular ... |
76-183 | 8.97e-12 | |||||||
gamma-aminobutyric acid receptor extracellular domain; This family contains extracellular domain (ECD) of type-A gamma-aminobutyric acid receptor (GABAAR), a member of the pentameric "Cys-loop" superfamily of transmitter-gated ion channels. This family includes 19 isoforms in human; six alpha, 3 beta, 3 gamma, one of delta, epsilon, pi, and theta, known to form heteropentameric GABAARs, and 3 rho subunits that only form homopentameric channels (also known as GABAA rho or GABAC receptor) or pseudoheteromeric if consisting of different rho subunits. The majority of GABAA receptor pentamers contain two alpha subunits, two beta subunits, and a gamma subunit, with different isoforms affecting potency of the neurotransmitter. GABAAR is an anionic channel, mediating fast inhibitory synaptic transmission. Upon gamma-aminobutyric acid (GABA) binding to its site on the ECD, Cl- ions are selectively conducted through the GABAAR pore, resulting in hyperpolarization of the neuron. GABAAR is the principal mediator of rapid inhibitory synaptic transmission in the human brain. Benzodiazepine and barbiturates each bind to their own distinct sites on the ECD. The channels have to contain the gamma subunit and alpha subunits in order to respond to benzodiazepines. Specific combinations of alpha, beta, and gamma subunits exhibit ethanol sensitivity. All these major classes of drugs favor channel-opening. A decline in GABAAR signaling triggers hyperactive neurological disorders such as insomnia, anxiety, and epilepsy. Pssm-ID: 349791 [Multi-domain] Cd Length: 184 Bit Score: 63.73 E-value: 8.97e-12
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| LGIC_ECD_GABAAR_delta | cd19001 | extracellular domain of gamma-aminobutyric acid receptor subunit delta; This family contains ... |
54-181 | 1.94e-11 | |||||||
extracellular domain of gamma-aminobutyric acid receptor subunit delta; This family contains extracellular domain of delta subunit of type-A gamma-aminobutyric acid receptor (GABAAR). GABAAR is an anionic channel, mediating fast inhibitory synaptic transmission. Upon gamma-aminobutyric acid (GABA) binding to the ligand binding site on the ECD, Cl- ions are selectively conducted through the GABAAR pore, resulting in hyperpolarization of the neuron. GABAAR is the principal mediator of rapid inhibitory synaptic transmission in the human brain. A decline in GABAAR signaling triggers hyperactive neurological disorders such as insomnia, anxiety, and epilepsy. Receptors containing the delta subunit (GABRD) are expressed exclusively extra-synaptically (in the cortex, hippocampus, thalamus, striatum, and cerebellum) and mediate tonic inhibition. Studies suggest that delta subunits form heteropentamers in similar stoichiometry and arrangement as alpha/beta/gamma receptors, with the delta subunit replacing the gamma subunit (2alpha:2beta:1delta), although other stoichiometries have also been detected. The delta subunit is flexible in its positioning in the pentameric complex, producing receptors with diverse pharmacological properties. Mutations in GABRD have been associated with susceptibility to generalized epilepsy with febrile seizures, type 5. GABRD gene may also be associated with childhood-onset mood disorders. Pssm-ID: 349802 Cd Length: 184 Bit Score: 62.78 E-value: 1.94e-11
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| LGIC_ECD_GABAAR_A5 | cd19038 | extracellular domain of gamma-aminobutyric acid receptor subunit alpha-5 (GABAAR-A5 or GABRA5); ... |
40-181 | 2.94e-11 | |||||||
extracellular domain of gamma-aminobutyric acid receptor subunit alpha-5 (GABAAR-A5 or GABRA5); This family contains extracellular domain of gamma-aminobutyric acid receptor subunit alpha-5 (GABAAR-A5), a protein that is encoded by the GABRA5 gene in humans, with biased expression in the brain and heart. GABAAR is an anionic channel, mediating fast inhibitory synaptic transmission. Upon gamma-aminobutyric acid (GABA) binding to the ligand binding site on the ECD, Cl- ions are selectively conducted through the GABAAR pore, resulting in hyperpolarization of the neuron. GABAAR is the principal mediator of rapid inhibitory synaptic transmission in the human brain. A decline in GABAAR signaling triggers hyperactive neurological disorders such as insomnia, anxiety, and epilepsy. The alpha-5 subunit forms heteropentamers with other GABAAR subunits, most broadly expressed as alpha5-beta-gamma2, and probably alpha5-beta3-gamma2, predominantly expressed in the hippocampus and localized extrasynaptically. These receptors have been demonstrated to play an important modulatory role in learning and memory processes, thus making them suitable targets for pharmacological intervention. Studies show that alpha5-containing GABAARs play an important part in tonic inhibition in hippocampal pyramidal neurons, and that these can also contribute to synaptic inhibition. Studies strongly suggest that amnesia is primarily mediated by alpha5-beta-gamma2. Polymorphisms in GABRA5 (and GABRA3) are linked to the susceptibility to panic disorder. A genetic association also exists between GABRA5 and bipolar affective disorder. Pssm-ID: 349839 Cd Length: 199 Bit Score: 62.76 E-value: 2.94e-11
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| LGIC_ECD_GABAAR_LCCH3-like | cd19006 | gamma-aminobutyric acid receptor subunit beta-like extracellular domain in protostomia, such ... |
56-183 | 5.11e-11 | |||||||
gamma-aminobutyric acid receptor subunit beta-like extracellular domain in protostomia, such as LCCH3 (ligand-gated chloride channel homolog 3); This family contains extracellular domain of beta-like subunits of type-A gamma-aminobutyric acid receptor (GABAAR) found in protostomia, similar to Drosophila melanogaster ligand-gated chloride channel homolog 3 (LCCH3) subunits. Drosophila melanogaster expresses three GABA-receptor subunit orthologs: (RDL, resistant to dieldrin; GRD, GABA/glycine-like receptor of Drosophila; LCCH3, ligand-gated chloride channel homolog 3), and may possibly form homo- and/or heteropentameric associations. LCCH3 has been shown to combine with subunit GRD to form cation-selective GABA-gated ion channels when coexpressed in Xenopus laevis oocytes. GABAARs are known to be the molecular targets of a class of insecticides. The resulting pentameric receptors in this family have been shown to be activated by insect GABA-receptor agonists muscimol and CACA, and blocked by antagonists fipronil, dieldrin, and picrotoxin, but not bicuculline. GABAARs are abundant in the CNS, where their physiological role is to mediate fast inhibitory neurotransmission. In insects, this inhibitory transmission plays a crucial role in olfactory information processing. Pssm-ID: 349807 Cd Length: 183 Bit Score: 61.32 E-value: 5.11e-11
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| LGIC_ECD_GABAAR_B | cd18999 | extracellular domain of gamma-aminobutyric acid receptor subunit beta (GABAAR-B or GABRB); ... |
54-182 | 7.23e-11 | |||||||
extracellular domain of gamma-aminobutyric acid receptor subunit beta (GABAAR-B or GABRB); This family contains extracellular domain (ECD) of beta subunits of type-A gamma-aminobutyric acid receptor (GABAAR), which include beta1-beta4 in vertebrates. GABAAR is an anionic channel, mediating fast inhibitory synaptic transmission. Upon gamma-aminobutyric acid (GABA) binding to the ECD, Cl- ions are selectively conducted through the GABAAR pore, resulting in hyperpolarization of the neuron. GABAAR is the principal mediator of rapid inhibitory synaptic transmission in the human brain. Benzodiazepine and barbiturates each bind to their own distinct sites on the LBD. The channels must contain the gamma subunit and alpha subunits in order to respond to benzodiazepines. Specific combinations of alpha, beta, and gamma subunits exhibit ethanol sensitivity. All these major classes of drugs favor channel-opening. A decline in GABAAR signaling triggers hyperactive neurological disorders such as insomnia, anxiety, and epilepsy. Mutations or genetic variations of the genes encoding the GABRB2 and GABRB3 have been associated with human epilepsy, both with and without febrile seizures. Mutations in GABRB2, and GABRB3 have been associated with infantile spasms and Lennox-Gastaut syndrome. A de novo missense mutation of GABRB2 causes early myoclonic encephalopathy, a disease with a devastating prognosis, characterized by neonatal onset of seizures. Another de novo heterozygous missense variant in exon 4 of GABRB2 is associated with intellectual disability and epilepsy. Mutations in the GABRB1 gene promote alcohol consumption through increased tonic inhibition. Pssm-ID: 349800 Cd Length: 182 Bit Score: 61.14 E-value: 7.23e-11
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| LGIC_TM_5-HT3 | cd19063 | transmembrane domain of 5-hydroxytryptamine 3 (5-HT3) receptor; This family contains ... |
233-321 | 8.09e-11 | |||||||
transmembrane domain of 5-hydroxytryptamine 3 (5-HT3) receptor; This family contains transmembrane (TM) domain of the serotonin 5-HT3 receptors. The transmembrane region consists of four transmembrane-spanning alpha-helical segments (M1-M4) that are linked by loops. The intracellular loop that links M1 and M2 determines the ion selectivity of the channel. The 5-HT3 channel is cation-selective and mediates neuronal depolarization and excitation within the central and peripheral nervous systems. Like other ligand gated ion channels, the 5-HT3 receptor consists of five subunits arranged around a central ion conducting pore, which is permeable to Na+, K+, and Ca2+ ions. Binding of the neurotransmitter 5-hydroxytryptamine (serotonin) to the 5-HT3 receptor opens the channel, which then leads to an excitatory response in neurons, and the rapidly activating, desensitizing, inward current is predominantly carried by Na+ and K+ ions. This receptor is most closely related by homology to the nicotinic acetylcholine receptor (nAChR). Five subunits have been identified for this family: 5-HT3A, 5-HT3B, 5-HT3C, 5-HT3D, and 5-HT3E, encoded by HTR3A-E genes. Only 5-HT3A subunits are able to form functional homomeric receptors, whereas the 5-HT3B, C, D, and E subunits form heteromeric receptors with 5-HT3A. Different receptor subtypes are important mediators of nausea and vomiting during chemotherapy, pregnancy, and following surgery, while some contribute to neuro-gastroenterologic disorders such irritable bowel syndrome (IBS) and eating disorders as well as co-morbid psychiatric conditions. 5-HT3 receptor antagonists are established treatments for emesis and IBS, and are beneficial in the treatment of psychiatric diseases. Pssm-ID: 349865 Cd Length: 121 Bit Score: 59.18 E-value: 8.09e-11
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| LGIC_ECD_ZAC | cd18994 | extracellular domain of zinc-activated ligand-gated ion channel; This family is the ... |
56-224 | 8.53e-11 | |||||||
extracellular domain of zinc-activated ligand-gated ion channel; This family is the extracellular domain of zinc-activated ligand-gated ion channel (ZAC), a cationic ion channel belonging to the superfamily of Cys-loop receptors, which consists of pentameric ligand-gated ion channels. ZAC displays low sequence similarity to other members in the superfamily, with closest matches to the human serotonin 5-HT3 receptor (5-HT3R) subunits 5-HT3A and 5-HT3B, and nAChR alpha7 subunits that exhibit approximately 15% amino acid sequence identity to ZAC. Expression of ZAC has been detected in human fetal whole brain, spinal cord, pancreas, placenta, prostate, thyroid, trachea, and stomach, as well as in adult hippocampus, striatum, amygdala, and thalamus. ZAC forms an ion channel gated by Zn2+, Cu2+, and H+, and is non-selectively permeable to monovalent cations. However, the role of ZAC in Zn2+, Cu2+, and H+ signaling is as yet unknown. Pssm-ID: 349795 Cd Length: 170 Bit Score: 60.56 E-value: 8.53e-11
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| LGIC_ECD_GABAAR_A6 | cd19039 | extracellular domain of gamma-aminobutyric acid receptor subunit alpha-6 (GABAAR-A6 or GABRA6); ... |
40-181 | 9.17e-11 | |||||||
extracellular domain of gamma-aminobutyric acid receptor subunit alpha-6 (GABAAR-A6 or GABRA6); This family contains extracellular domain of gamma-aminobutyric acid receptor subunit alpha-6 (GABAAR-A6), a protein that is encoded by the GABRA6 gene in humans. GABAAR is an anionic channel, mediating fast inhibitory synaptic transmission. Upon gamma-aminobutyric acid (GABA) binding to the ligand binding site on the ECD, Cl- ions are selectively conducted through the GABAAR pore, resulting in hyperpolarization of the neuron. GABAAR is the principal mediator of rapid inhibitory synaptic transmission in the human brain. A decline in GABAAR signaling triggers hyperactive neurological disorders such as insomnia, anxiety, and epilepsy. The alpha-6 subunit forms heteropentamers with other GABAAR subunits, most broadly expressed as alpha6-beta-gamma2 found extrasynaptically, alpha6-beta2/3-delta in the cerebellar granule cells and likely also forms alpha1-alpha6-beta-gamma/alpha1-alpha6-beta-delta. A GABRA6 mutation from Arg to Trp, has been identified as a susceptibility gene that may contribute to the pathogenesis of childhood absence epilepsy and cause neuronal disinhibition and increase in seizures via a reduction of alphabetagamma and alphabetadelta receptor function and expression. Polymorphism in the GABRA6 gene is associated with specific personality characteristics as well as a marked attenuation in hormonal and blood pressure responses to psychological stress. Alpha6-containing receptors lack high sensitivity to diazepam. Pssm-ID: 349840 Cd Length: 198 Bit Score: 61.19 E-value: 9.17e-11
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| LGIC_ECD_GABAAR_rho | cd19005 | extracellular domain of gamma-aminobutyric acid receptor subunit rho; This family contains ... |
54-185 | 1.05e-10 | |||||||
extracellular domain of gamma-aminobutyric acid receptor subunit rho; This family contains extracellular domain of rho subunits (rho1, rho2, and rho3, encoded by GABRR1, GABRR2, and GABRR3, respectively) of type-A gamma-aminobutyric acid receptor (GABAAR). These subunits homo-oligomerize to form GABAA-rho receptors (formerly classified as GABA-rho or GABAC receptor), but do not co-assemble with any of the classical GABAA subunits. They are especially high expression in the retina and their distinctive pharmacological properties are unique; they are not modulated by many GABAA receptor modulators such as barbiturates, benzodiazepines, and neuroactive steroids. In humans, mutations in the GABRR1 and GABRR2 genes may be responsible for some cases of autosomal recessive retinitis pigmentosa. Variation in GABRR1 is also associated with susceptibility to bipolar schizoaffective disorder while a SNP in GABRR2 has been reported to show association with autism. Pssm-ID: 349806 Cd Length: 186 Bit Score: 60.80 E-value: 1.05e-10
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| LGIC_ECD_GABAAR_rho2 | cd19047 | extracellular domain of gamma-aminobutyric acid receptor subunit rho-2 (GABA-rho2 or GABRR2); ... |
54-185 | 1.43e-10 | |||||||
extracellular domain of gamma-aminobutyric acid receptor subunit rho-2 (GABA-rho2 or GABRR2); This family contains extracellular domain (ECD) of the rho subunit 2 of type-A gamma-aminobutyric acid receptor (GABAAR), encoded by the GABRR2 gene which exists next to GABRR1 (encoding rho subunit 1) on the chromosome region thought to be associated with susceptibility for psychiatric disorders and epilepsy. Close proximity of the rho1 and rho2 subunit genes suggests that they emerged via a local duplication event. Rho1 is expressed in many areas of the brain, but especially high in the retina. This subunit homo-oligomerizes to form GABAA-rho receptors (formerly classified as GABA-rho or GABAc receptor), but does not co-assemble with any of the classical GABAAR subunits. In humans, mutations in the GABRR2 gene may be responsible for some cases of autosomal recessive retinitis pigmentosa. Variation in GABRR2 is also associated with susceptibility to bipolar schizoaffective disorder, as well as alcohol dependence and general cognitive ability. GABA-rho2 receptors expressed pre-synaptically in the spinal dorsal horn have been implicated in pain perception and identified as a novel target for analgesia. Pssm-ID: 349848 Cd Length: 186 Bit Score: 60.11 E-value: 1.43e-10
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| LGIC_ECD_bact | cd18988 | extracellular domain of prokaryotic pentameric ligand-gated ion channels (pLGIC); This family ... |
60-231 | 2.20e-10 | |||||||
extracellular domain of prokaryotic pentameric ligand-gated ion channels (pLGIC); This family contains extracellular domain (ECD) of bacterial pentameric ligand-gated ion channels (pLGICs), including ones from Gloebacter violaceus (GLIC) and Erwinia chrysanthemi (ELIC). These prokaryotic homologs of Cys-loop receptors have been useful in understanding their eukaryotic counterparts. The largely beta-sheet ECD in this family is similar to other pLGICs, but lacks the cysteine loop and an intracellular domain. While most pLGICs undergo desensitization on prolonged exposure to the agonist, GLIC is activated by protons, but does not desensitize, even at proton concentrations eliciting maximal electrophysiological response (pH 4.5). Studies show that GLIC activation is inhibited by most general anaesthetics at clinical concentrations, including xenon which has been used in clinical practice as a potent gaseous anesthetic for decades. Xenon binding sites have been identified in three distinct regions of the TMD: in a large intra-subunit cavity, in the pore, and at the interface between adjacent subunits. Pssm-ID: 349789 Cd Length: 182 Bit Score: 59.61 E-value: 2.20e-10
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| LGIC_ECD_GABAAR_A4 | cd19037 | extracellular domain of gamma-aminobutyric acid receptor subunit alpha-4 (GABAAR-A4 or GABRA4); ... |
40-181 | 3.03e-10 | |||||||
extracellular domain of gamma-aminobutyric acid receptor subunit alpha-4 (GABAAR-A4 or GABRA4); This family contains extracellular domain of gamma-aminobutyric acid receptor subunit alpha-4 (GABAAR-A4), a protein that is encoded by the GABRA4 gene in humans, with biased expression in the brain and heart. GABAAR is an anionic channel, mediating fast inhibitory synaptic transmission. Upon gamma-aminobutyric acid (GABA) binding to the ligand binding site on the ECD, Cl- ions are selectively conducted through the GABAAR pore, resulting in hyperpolarization of the neuron. GABAAR is the principal mediator of rapid inhibitory synaptic transmission in the human brain. A decline in GABAAR signaling triggers hyperactive neurological disorders such as insomnia, anxiety, and epilepsy. The alpha-4 subunit forms heteropentamers with other GABAAR subunits, most broadly expressed as combination of alpha2alpha4beta1gamma1, all four subunits existing on the same gene cluster. Alpha-4 is involved in the etiology of autism and eventually increases autism risk through interaction with the beta-1 (GABRB1) subunit. Polymorphism in GABRA4 may trigger migraine by ethanol, while another is associated to faster reaction times and with lower ethanol effects. A rare variant in GABRA4 may have modest physiological effect in autism spectrum disorder etiology. Pssm-ID: 349838 Cd Length: 199 Bit Score: 59.69 E-value: 3.03e-10
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| LGIC_ECD_GABAAR_A | cd18998 | extracellular domain of gamma-aminobutyric acid receptor subunit alpha; This family contains ... |
68-231 | 3.34e-10 | |||||||
extracellular domain of gamma-aminobutyric acid receptor subunit alpha; This family contains extracellular domain (ECD) of type-A gamma-aminobutyric acid receptor (GABAAR), a member of the pentameric "Cys-loop" superfamily of transmitter-gated ion channels. This family includes 19 isoforms in human; six alpha, 3 beta, 3 gamma, one of delta, epsilon, pi, and theta, known to form heteromeric GABAARs, and 3 rho subunits that only form homomeric channels (also known as GABAA rho or GABAC receptor) or pseudoheteromeric if consisting of different rho subunits. GABAAR is assembled from a variety of different subunit subtypes which determines their pharmacology and physiology; the most abundant being 2alpha2beta1gamma stoichiometry. GABAAR is an anionic channel, mediating fast inhibitory synaptic transmission. Upon gamma-aminobutyric acid (GABA) binding to its site on the ECD, Cl- ions are selectively conducted through the GABAAR pore, resulting in hyperpolarization of the neuron. GABAAR is the principal mediator of rapid inhibitory synaptic transmission in the human brain. Benzodiazepine and barbiturates each bind to their own distinct sites on the ECD. The channels have to contain the gamma subunit and alpha subunits in order to respond to benzodiazepines. All these major classes of drugs favor channel-opening. A decline in GABAAR signaling triggers hyperactive neurological disorders such as insomnia, anxiety, and epilepsy. GABRA1, GABRA3, GABRB3, GABRG2, and GABRD, encoding the alpha1-, alpha3-, beta2-, gamma3-, and delta-subunits have been directly associated with epilepsy. Specific combinations of alpha, beta, and gamma subunits exhibit ethanol sensitivity. Pssm-ID: 349799 Cd Length: 184 Bit Score: 59.08 E-value: 3.34e-10
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| LGIC_ECD_GABAAR_rho1 | cd19046 | extracellular domain of gamma-aminobutyric acid receptor subunit rho-1 (GABA-rho1 or GABRR1); ... |
54-185 | 9.27e-10 | |||||||
extracellular domain of gamma-aminobutyric acid receptor subunit rho-1 (GABA-rho1 or GABRR1); This family contains extracellular domain (ECD) of the rho subunit 1 of type-A gamma-aminobutyric acid receptor (GABAAR), encoded by the GABRR1 gene, expressed in many areas of the brain, but especially high in the retina. GABRR1 exists next to GABRR2 (encoding rho subunit 2) on the chromosome region thought to be associated with susceptibility for psychiatric disorders and epilepsy. Close proximity of the rho1 and rho2 subunit genes suggests that they emerged via a local duplication event. This subunit homo-oligomerizes to form GABAA-rho receptors (formerly classified as GABA-rho or GABAc receptor), but does not co-assemble with any of the classical GABAAR subunits. In humans, mutations in the GABRR1 gene may be responsible for some cases of autosomal recessive retinitis pigmentosa. Variation in GABRR1 is also associated with susceptibility to bipolar schizoaffective disorder, and may be associated with alcohol dependency. Pssm-ID: 349847 Cd Length: 186 Bit Score: 57.80 E-value: 9.27e-10
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| LGIC_ECD_GABAAR_A1 | cd19034 | extracellular domain of gamma-aminobutyric acid receptor subunit alpha-1 (GABAAR-A1 or GABRA1); ... |
44-231 | 1.83e-09 | |||||||
extracellular domain of gamma-aminobutyric acid receptor subunit alpha-1 (GABAAR-A1 or GABRA1); This family contains extracellular domain of gamma-aminobutyric acid receptor subunit alpha-1 (GABAAR-A1), a protein that is encoded by the GABRA1 gene in humans. GABAAR is an anionic channel, mediating fast inhibitory synaptic transmission. Upon gamma-aminobutyric acid (GABA) binding to the ligand binding site on the ECD, Cl- ions are selectively conducted through the GABAAR pore, resulting in hyperpolarization of the neuron. GABAAR is the principal mediator of rapid inhibitory synaptic transmission in the human brain. A decline in GABAAR signaling triggers hyperactive neurological disorders such as insomnia, anxiety, and epilepsy. The alpha-1 subunits form heteropentamers with other GABAAR subunits, most broadly expressed as combination of two alpha1, beta1, gamma. Alpha1, beta2, and gamma2 subunits are clustered on the same human chromosome and may be why alpha1beta2gamma2 receptors are one of the most abundant GABAA receptor isoforms in CNS neurons. Mutations in this gene cause familial juvenile myoclonic epilepsy, sporadic childhood absence epilepsy type 4, and idiopathic familial generalized epilepsy. Polymorphisms in GABRA1 are also significantly associated with schizophrenia. GABRA1 has also been associated with methamphetamine abuse. The GABRA1 receptor is the specific target of the z-drug class of nonbenzodiazepine hypnotic agents and is responsible for their hypnotic and hallucinogenic effects. Pssm-ID: 349835 Cd Length: 194 Bit Score: 57.39 E-value: 1.83e-09
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| LGIC_ECD_GABAAR_B1 | cd19040 | extracellular domain of gamma-aminobutyric acid receptor subunit beta-1 (GABAAR-B1 or GABRB1); ... |
54-182 | 2.62e-09 | |||||||
extracellular domain of gamma-aminobutyric acid receptor subunit beta-1 (GABAAR-B1 or GABRB1); This family contains extracellular domain (ECD) of gamma-aminobutyric acid receptor beta-1 subunit, a protein that is encoded by the GABRB1 gene. GABAAR is an anionic channel, mediating fast inhibitory synaptic transmission. Upon gamma-aminobutyric acid (GABA) binding to the ligand binding site on the ECD, Cl- ions are selectively conducted through the GABAAR pore, resulting in hyperpolarization of the neuron. GABAAR is the principal mediator of rapid inhibitory synaptic transmission in the human brain. A decline in GABAAR signaling triggers hyperactive neurological disorders such as insomnia, anxiety, and epilepsy. The beta-1 subunit forms heteropentamers with other GABAAR subunits, likely expressed as alpha-beta1-gamma/delta, mainly found in the brain. It is clustered on the chromosome with genes encoding alpha 4, alpha 2, and gamma 1 subunits of the GABAAR. GABRB1 expression is altered significantly in the lateral cerebellum of subjects with schizophrenia, major depression, and bipolar disorder. Mutations in the GABRB1 gene promote alcohol consumption through increased tonic inhibition. Epigenetic control of gene expression may affect the expression of GABRB1 and disrupt inhibitory synaptic transmission during embryonic development. The GABRB1 gene is also associated with thalamus volume and modulates the association between thalamus volume and intelligence. Pssm-ID: 349841 Cd Length: 182 Bit Score: 56.57 E-value: 2.62e-09
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| LGIC_ECD_GABAAR_rho3 | cd19048 | extracellular domain of gamma-aminobutyric acid receptor subunit rho-3 (GABAA-rho3); This ... |
54-181 | 3.17e-09 | |||||||
extracellular domain of gamma-aminobutyric acid receptor subunit rho-3 (GABAA-rho3); This family contains extracellular domain (ECD) of the rho subunit 3 of type-A gamma-aminobutyric acid receptor (GABAAR), encoded by the GABRR3 gene which maps to a different chromosome to that of GABRR1 and GABRR2. While close proximity of the rho1 and rho2 subunit genes suggests that they emerged via a local duplication event, GABRR3 may have arisen by duplication of a GABRR1/GABRR2 progenitor. This subunit homo-oligomerizes to form GABAA-rho receptors (formerly classified as GABA-rho or GABAc receptor), but does not co-assemble with any of the classical GABAAR subunits. In humans, some individuals contain a variant that is predicted to inactivate this gene product. Pssm-ID: 349849 Cd Length: 186 Bit Score: 56.20 E-value: 3.17e-09
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| LGIC_ECD_GABAAR_B2 | cd19041 | extracellular domain of gamma-aminobutyric acid receptor subunit beta-2 (GABAAR-B2 or GABRB2); ... |
54-182 | 3.58e-09 | |||||||
extracellular domain of gamma-aminobutyric acid receptor subunit beta-2 (GABAAR-B2 or GABRB2); This family contains extracellular domain (ECD) of gamma-aminobutyric acid receptor beta-2 subunit, a protein that is encoded by the GABRB2 gene. GABAAR is an anionic channel, mediating fast inhibitory synaptic transmission. Upon gamma-aminobutyric acid (GABA) binding to the ligand binding site on the ECD, Cl- ions are selectively conducted through the GABAAR pore, resulting in hyperpolarization of the neuron. GABAAR is the principal mediator of rapid inhibitory synaptic transmission in the human brain. A decline in GABAAR signaling triggers hyperactive neurological disorders such as insomnia, anxiety, and epilepsy. The beta-2 subunit forms heteropentamers with other GABAAR subunits, with alpha1-beta2-gamma2 subtype being the most prevalent isoform (approximately 50%-60% of all GABAARs), and are expressed in almost all regions of the brain. It also assembles less abundantly as alpha4beta2/3delta and alpha6beta2/3delta. Mutations or genetic variations of the genes encoding the GABRB2 and GABRB3 have been associated with human epilepsy, both with and without febrile seizures. Mutations in GABRB2, and GABRB3 have been associated with infantile spasms and Lennox-Gastaut syndrome. A de novo missense mutation of GABRB2 causes early myoclonic encephalopathy, a disease with a devastating prognosis, characterized by neonatal onset of seizures. Another de novo heterozygous missense variant in exon 4 of GABRB2 is associated with intellectual disability and epilepsy. GABRB2 plays important tumorigenic functions and acts as a novel oncogene in papillary thyroid carcinoma (PTC). Pssm-ID: 349842 Cd Length: 182 Bit Score: 56.20 E-value: 3.58e-09
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| LGIC_ECD_GABAAR_G | cd19000 | extracellular domain of gamma-aminobutyric acid receptor subunit gamma; This family contains ... |
76-181 | 6.33e-09 | |||||||
extracellular domain of gamma-aminobutyric acid receptor subunit gamma; This family contains extracellular domain (ECD) of the theta subunit of type-A gamma-aminobutyric acid receptor (GABAAR). GABAAR is an anionic channel, mediating fast inhibitory synaptic transmission. Cl- ions are selectively conducted through the GABAAR pore, resulting in hyperpolarization of the neuron. GABAAR is the principal mediator of rapid inhibitory synaptic transmission in the human brain. A decline in GABAAR signaling triggers hyperactive neurological disorders such as insomnia, anxiety, and epilepsy. GABA stimulates human hepatocellular carcinoma growth through overexpressed GABAA receptor theta subunit. Also, two autism spectrum disorder (ASD)-associated protein truncation variants have been identified in alpha 3 (GABRA3) and theta (GABRQ) genes. Pssm-ID: 349801 Cd Length: 182 Bit Score: 55.32 E-value: 6.33e-09
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| LGIC_ECD_GABAAR_B3 | cd19042 | extracellular domain of gamma-aminobutyric acid receptor subunit beta-3 (GABAAR-B3 or GABRB3); ... |
54-182 | 1.58e-08 | |||||||
extracellular domain of gamma-aminobutyric acid receptor subunit beta-3 (GABAAR-B3 or GABRB3); This family contains extracellular domain (ECD) of gamma-aminobutyric acid receptor beta-3 subunit, a protein that is encoded by the GABRB3 gene. GABAAR is an anionic channel, mediating fast inhibitory synaptic transmission. Upon gamma-aminobutyric acid (GABA) binding to the ligand binding site on the ECD, Cl- ions are selectively conducted through the GABAAR pore, resulting in hyperpolarization of the neuron. GABAAR is the principal mediator of rapid inhibitory synaptic transmission in the human brain. A decline in GABAAR signaling triggers hyperactive neurological disorders such as insomnia, anxiety, and epilepsy. The beta-3 subunit forms heteropentamers with other GABAAR subunits, with alpha2-beta3-gamma2 and alpha3-beta3-gamma2 subtypes highly enriched in hippocampal pyramidal neurons and cholinergic neurons of the basal forebrain, respectively. Other heteromers include alpha1-beta3-gamma2 and alpha5-beta3-gamma2. GABRB3 mutations are likely associated with a broad phenotypic spectrum of epilepsies and that reduced receptor function causing GABAergic disinhibition represents the relevant disease mechanism. GABRB3 might be associated with heroin dependence, and increased expression possibly contributing to the pathogenesis of heroin dependence. This gene may also be associated with the pathogenesis of other disorders such as Angelman syndrome, Prader-Willi syndrome, nonsyndromic orofacial clefts, schizophrenia, and autism. Pssm-ID: 349843 Cd Length: 183 Bit Score: 54.26 E-value: 1.58e-08
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| LGIC_ECD_GlyR_alpha | cd19009 | extracellular domain of glycine receptor alpha subunit; This subfamily contains extracellular ... |
67-203 | 1.88e-08 | |||||||
extracellular domain of glycine receptor alpha subunit; This subfamily contains extracellular domain of glycine receptor (GlyR or GLR) alpha subunits of the amino acid neurotransmitter glycine. GlyR has four known isoforms of alpha-subunit (alpha1-4, encoded by GLRA1, GLRA2, GLRA3, GLRA4) that are essential to bind ligands, and, along with the GlyR beta subunit, have been described to have a regionally and temporally controlled expression during development and maturation of the central nervous system (CNS). These alpha subunits are highly homologous, but differ in their kinetic properties, temporal and regional expression and physiological functions. They can form functional chloride-permeable GlyR ion channels by forming homopentamers with 5 alpha subunits or heteropentamers with a combination of alpha and beta subunits, either a 2alpha-3beta or 3alpha-2beta stoichiometry. In human, mutations in glycine receptor alpha subunits cause disruption of GlyR surface expression or reduced ability of expressed GlyRs to conduct chloride ions. Mutations in GlyR alpha1 subunit leads to hyperekplexia, a rare neurological disorder characterized by neonatal hypertonia and exaggerated startle responses to unexpected stimuli, while mutations in GlyR alpha2 are known to cause cortical neuronal migration/autism spectrum disorder and in GlyR alpha3 to cause inflammatory pain sensitization/rhythmic breathing. GlyR alpha1 and alpha2 subunits have an important role in regulation of the excitatory-inhibitory balance, control of motor actions, modulation of sedative ethanol effects and probably regulation ethanol preference and consumption. Pssm-ID: 349810 Cd Length: 184 Bit Score: 54.21 E-value: 1.88e-08
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| LGIC_ECD_GABAAR_G2 | cd19044 | extracellular domain of gamma-aminobutyric acid receptor subunit gamma-2 (GABAAR-G2 or GABRG2); ... |
68-181 | 2.86e-08 | |||||||
extracellular domain of gamma-aminobutyric acid receptor subunit gamma-2 (GABAAR-G2 or GABRG2); This family contains extracellular domain of gamma-aminobutyric acid receptor subunit gamma-2 (GABAAR-G2), a protein that is encoded by the GABRG2 gene in humans. GABAAR is an anionic channel, mediating fast inhibitory synaptic transmission. Upon gamma-aminobutyric acid (GABA) binding to the ligand binding site on the ECD, Cl- ions are selectively conducted through the GABAAR pore, resulting in hyperpolarization of the neuron. GABAAR is the principal mediator of rapid inhibitory synaptic transmission in the human brain. A decline in GABAAR signaling triggers hyperactive neurological disorders such as insomnia, anxiety, and epilepsy. The gamma-2 subunit forms heteropentamers with other GABAAR subunits, most prevalently expressed as alpha1-beta2-gamma2. The gamma2 subunit also coassembles with other alpha and beta variants in the brain, but these receptors are found in considerably less abundance and are restricted in their regional, e.g. the alpha2-beta3-gamma2 and alpha3-beta3-gamma2 subtypes are highly enriched in hippocampal pyramidal neurons and cholinergic neurons of the basal forebrain, respectively. Pathogenic missense and truncating variants in this gene have been associated with spectrum of epilepsies, from Dravet syndrome to milder simple febrile seizures, while a recurrent GABRG2 missense variant is associated with early-onset seizures, significant motor and speech delays, intellectual disability, hypotonia, movement disorder, dysmorphic features, and vision/ocular issues. Pssm-ID: 349845 Cd Length: 184 Bit Score: 53.52 E-value: 2.86e-08
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| LGIC_ECD_GlyR | cd18991 | extracellular domain of glycine receptor (GlyR); This subfamily contains extracellular domain ... |
67-177 | 3.21e-08 | |||||||
extracellular domain of glycine receptor (GlyR); This subfamily contains extracellular domain of glycine receptor (GlyR or GLR) of the amino acid neurotransmitter glycine. GlyR has four known isoforms of the alpha-subunit (alpha1-4, encoded by GLRA1, GLRA2, GLRA3, GLRA4) that are essential to bind ligands and a single beta-subunit (encoded by GLRB), all of which have been described to have a regionally and temporally controlled expression during development and maturation of the central nervous system (CNS). Functional chloride-permeable GlyR ion channels are formed by 5 alpha subunit homopentamers or by alpha and beta subunit heteropentamers, which form complexes with either a 2alpha-3beta or 3alpha-2beta stoichiometry. The receptor can be activated by glycine as well as beta-alanine and taurine, and can be selectively blocked by the high-affinity competitive antagonist strychnine. Caffeine is also a competitive antagonist of GlyR. In human, glycine receptor alpha1 and beta subunits are the major targets of mutations that cause disruption of GlyR surface expression or reduced ability of expressed GlyRs to conduct chloride ions, leading to hyperekplexia, a rare neurological disorder characterized by neonatal hypertonia and exaggerated startle responses to unexpected stimuli. Mutations in GlyR alpha2 are known to cause cortical neuronal migration/autism spectrum disorder and in GlyR alpha3 to cause inflammatory pain sensitization/rhythmic breathing. Pssm-ID: 349792 Cd Length: 185 Bit Score: 53.36 E-value: 3.21e-08
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| LGIC_ECD_GABAAR_G1 | cd19043 | extracellular domain of gamma-aminobutyric acid receptor subunit gamma-1 (GABAAR-G1 or GABRG1); ... |
76-194 | 4.84e-08 | |||||||
extracellular domain of gamma-aminobutyric acid receptor subunit gamma-1 (GABAAR-G1 or GABRG1); This family contains extracellular domain of gamma-aminobutyric acid receptor subunit gamma-1 (GABAAR-G1), a protein that is encoded by the GABRG1 gene in humans, clustered with the alpha2 gene GABRA2, which is associated with alcohol dependence. GABAAR is an anionic channel, mediating fast inhibitory synaptic transmission. Upon gamma-aminobutyric acid (GABA) binding to the ligand binding site on the ECD, Cl- ions are selectively conducted through the GABAAR pore, resulting in hyperpolarization of the neuron. GABAAR is the principal mediator of rapid inhibitory synaptic transmission in the human brain. A decline in GABAAR signaling triggers hyperactive neurological disorders such as insomnia, anxiety, and epilepsy. The gamma-1 subunit forms heteropentamers with other GABAAR subunits, likely expressed as combination of alpha1/2-beta-gamma1 subunits. A variant in GABRG1 shows the strongest statistical evidence of association of recovery from eating disorders. Studies show that upregulating or preserving GABAA gamma1/3 and gamma2 receptors may protect neurons against neurofibrillary pathology in Alzheimer's disease. Pssm-ID: 349844 Cd Length: 182 Bit Score: 52.74 E-value: 4.84e-08
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| LGIC_ECD_GABAAR_E | cd19002 | extracellular domain of gamma-aminobutyric acid receptor subunit epsilon (GABRE); This family ... |
53-181 | 5.62e-08 | |||||||
extracellular domain of gamma-aminobutyric acid receptor subunit epsilon (GABRE); This family contains extracellular domain of epsilon subunit of type-A gamma-aminobutyric acid receptor (GABAAR), a protein that is encoded by the GABRE gene in humans. GABAAR is an anionic channel, mediating fast inhibitory synaptic transmission. Upon gamma-aminobutyric acid (GABA) binding to the ligand binding site on the ECD, Cl- ions are selectively conducted through the GABAAR pore, resulting in hyperpolarization of the neuron. GABAAR is the principal mediator of rapid inhibitory synaptic transmission in the human brain. A decline in GABAAR signaling triggers hyperactive neurological disorders such as insomnia, anxiety, and epilepsy. The epsilon subunits form heteropentamers with other GABAAR subunits, possibly with alpha3, beta4, and theta subunits since their genes are clustered on the same human chromosome. Various combinations of alpha3-, theta-, and epsilon-subunits may be assembled at a regional and developmental level in the brain. Brainstem expression of epsilon subunit-containing GABAA receptors is upregulated during pregnancy, particularly in the ventral respiratory neurons, thus protecting breathing, despite increased neurosteroid levels during pregnancy. Pssm-ID: 349803 Cd Length: 182 Bit Score: 52.69 E-value: 5.62e-08
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| LGIC_ECD_GABAAR_G3 | cd19045 | extracellular domain of gamma-aminobutyric acid receptor subunit gamma-3 (GABAAR-G3 or GABRG3); ... |
61-181 | 1.01e-07 | |||||||
extracellular domain of gamma-aminobutyric acid receptor subunit gamma-3 (GABAAR-G3 or GABRG3); This family contains extracellular domain of gamma-aminobutyric acid receptor subunit gamma-3 (GABAAR-G3), a protein that is encoded by the GABRG3 gene in humans. GABAAR is an anionic channel, mediating fast inhibitory synaptic transmission. Upon gamma-aminobutyric acid (GABA) binding to the ligand binding site on the ECD, Cl- ions are selectively conducted through the GABAAR pore, resulting in hyperpolarization of the neuron. GABAAR is the principal mediator of rapid inhibitory synaptic transmission in the human brain. A decline in GABAAR signaling triggers hyperactive neurological disorders such as insomnia, anxiety, and epilepsy. The gamma-3 subunit forms heteropentamers with other GABAAR subunits, likely expressed as alpha1-beta3-gamma3. This subunit contains the benzodiazepine binding site. Polymorphisms in GABG3 show consistent evidence of alcohol dependence. Pssm-ID: 349846 Cd Length: 182 Bit Score: 51.98 E-value: 1.01e-07
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| LGIC_ECD_GABAR_GRD-like | cd19007 | gamma-aminobutyric acid receptor subunit alpha-like extracellular domain in protostomia, such ... |
68-181 | 1.44e-07 | |||||||
gamma-aminobutyric acid receptor subunit alpha-like extracellular domain in protostomia, such as GRD (GABA/glycine-like receptor of Drosophila); This family contains extracellular domain of alpha-like subunits of type-A gamma-aminobutyric acid receptor (GABAAR) found in protostomia, similar to Drosophila melanogaster GABA/ glycine-like receptor of Drosophila (GRD) subunits. Drosophila melanogaster expresses three GABA-receptor subunit orthologs: (RDL, resistant to dieldrin; GRD, GABA/glycine-like receptor of Drosophila; LCCH3, ligand-gated chloride channel homolog 3), and may possibly form homo- and/or heteropentameric associations. LCCH3 has been shown to combine with subunit GRD to form cation-selective GABA-gated ion channels when co-expressed in Xenopus laevis oocytes. GABAARs are known to be the molecular targets of a class of insecticides. The resulting pentameric receptors in this family have been shown to be activated by insect GABA-receptor agonists muscimol and CACA, and blocked by antagonists fipronil, dieldrin, and picrotoxin, but not bicuculline. GABAARs are abundant in the CNS, where their physiological role is to mediate fast inhibitory neurotransmission. In insects, this inhibitory transmission plays a crucial role in olfactory information processing. Pssm-ID: 349808 Cd Length: 183 Bit Score: 51.47 E-value: 1.44e-07
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| LGIC_ECD_GABAAR_theta | cd19003 | extracellular domain of gamma-aminobutyric acid receptor subunit theta (GABRQ); This family ... |
66-185 | 1.52e-06 | |||||||
extracellular domain of gamma-aminobutyric acid receptor subunit theta (GABRQ); This family contains extracellular domain (ECD) of the theta subunit of type-A gamma-aminobutyric acid receptor (GABAAR), and encoded by the GABRQ gene, which is mapped to chromosome Xq28 in a cluster of genes that also that encode the alpha 3 and epsilon subunits. The transmembrane region consists of four transmembrane-spanning alpha-helical segments (M1-M4) that are linked by loops. The intracellular loop that links M1 and M2 determines the ion selectivity of the channel. GABAAR is an anionic channel, mediating fast inhibitory synaptic transmission. Cl- ions are selectively conducted through the GABAAR pore, resulting in hyperpolarization of the neuron. GABAAR is the principal mediator of rapid inhibitory synaptic transmission in the human brain. A decline in GABAAR signaling triggers hyperactive neurological disorders such as insomnia, anxiety, and epilepsy. GABA stimulates human hepatocellular carcinoma growth through overexpressed GABAAR theta subunit. Also, two autism spectrum disorder (ASD)-associated protein truncation variants have been identified in alpha 3 (GABRA3) and theta (GABRQ) genes. Pssm-ID: 349804 Cd Length: 183 Bit Score: 48.45 E-value: 1.52e-06
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| LGIC_TM | cd03559 | transmembrane domain of Cys-loop neurotransmitter-gated ion channels; This superfamily ... |
234-324 | 2.77e-06 | |||||||
transmembrane domain of Cys-loop neurotransmitter-gated ion channels; This superfamily contains the transmembrane domain of Cys-loop neurotransmitter-gated ion channels, which include nicotinic acetylcholine receptor (nAChR), serotonin 5-hydroxytryptamine receptor (5-HT3), type-A gamma-aminobutyric acid receptor (GABAAR), and glycine receptor (GlyR). These ligand-gated ion channels (LGICs) are found across metazoans and have close homologs in bacteria. They are vital for communication throughout the nervous system where the sign of synaptic connections (excitatory or inhibitory) is determined by the charge of the ions that flow through these channels. In general, channels that conduct positive ions are excitatory, whereas channels that conduct negative ions are inhibitory. The transmembrane region consists of four transmembrane-spanning alpha-helical segments (M1-M4) that are linked by loops. The intracellular loop that links M1 and M2 determines the ion selectivity of the channel. GABAAR and GlyR are anionic channels, both mediating fast inhibitory synaptic transmission. Cl- ions are selectively conducted through the GABAAR receptor pore, resulting in hyperpolarization of the neuron. nAChR is a non-selective cation channel that is permeable to Na+ and K+, and some subunit combinations are also permeable to Ca2+. Na+ enters and K+ exits to allow net flow of positively charged ions inward. 5-HT3, a cation-selective channel, binds serotonin and is permeable to Na+, K+, and Ca2+. It mediates neuronal depolarization and excitation within the central and peripheral nervous systems. These ligand-gated chloride channels are critical not only for maintaining appropriate neuronal activity, but have long been important therapeutic targets: benzodiazepines, barbiturates, some intravenous and volatile anaesthetics, alcohol, strychnine, picrotoxin, and ivermectin all derive their biological activity from acting on the inhibitory half of the Cys-loop receptor family. Pssm-ID: 349850 Cd Length: 116 Bit Score: 46.37 E-value: 2.77e-06
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| LGIC_ECD_GlyR_beta | cd19010 | extracellular domain of glycine receptor beta subunit; This subfamily contains extracellular ... |
67-176 | 1.47e-05 | |||||||
extracellular domain of glycine receptor beta subunit; This subfamily contains extracellular domain of glycine receptor (GlyR or GLR) beta subunit of the amino acid neurotransmitter glycine encoded by GLRB gene. These subunits form heteropentamers with a combination of alpha and beta subunits, either a 2alpha-3beta or 3alpha-2beta stoichiometry. While the alpha subunits contain binding sites for agonists and antagonists and are responsible for ion channel formation, the beta subunit displays structural and regulatory functions, such as GlyR clustering in synaptic locations by interaction between intracellular loop domains with the scaffolding protein gephyrin, and control of pharmacologic responses to agonist or allosteric modulators due in part to the presence of interfaces alpha/beta and beta/beta. GLRB gene mutations are associated with the neurological disorder hyperekplexia, a rare neurological disorder characterized by neonatal hypertonia and exaggerated startle responses to unexpected stimuli, as well as agoraphobic cognitions. Pssm-ID: 349811 Cd Length: 187 Bit Score: 45.78 E-value: 1.47e-05
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| LGIC_ECD_HisCl | cd18992 | extracellular domain of histimine-gated chloride channel (HisCl or HGCC); This family contains ... |
59-185 | 2.21e-05 | |||||||
extracellular domain of histimine-gated chloride channel (HisCl or HGCC); This family contains extracellular domain (ECD) of histamine-gated chloride channel (HisCl), a member of the Cys-loop receptor superfamily of ligand-gated ion channels and is closely related to the mammalian GABAA receptor and glycine receptor (GlyR). Histamine (HA) is a neurotransmitter that activates GPCRs in vertebrates, but in arthropods, it is a photoreceptor neurotransmitter, directly gating chloride channels on large monopolar cells (LMCs), postsynaptic to photoreceptors in the lamina. It has also been reported to play important roles in mechanosensory reception, temperature preference, and sleep in insects. HA activates its receptor channels to cause an inward chloride flux in the insect nervous system. In Drosophila, HA acts on two histamine-gated chloride channel (HGCC) subunits called HisCl1 (HisClalpha2, HCLB) and HisCl2 (HisClalpha1, Ort, HCLA). HisCl1 (HCLB) and HisCl2 (HCLA) are expressed predominantly in the insect eye, sharing 60% sequence identity, and forming homomeric and heteromeric HGCCs. HCLA homomers are involved in synaptic transmission in the lamina, while HCLB homomers, localized in the glia cells, have a role in shaping the transmission. HCLB channels, but not HCLA channels, are also responsible for the activation and maintenance of wake state in D. melanogaster. In Manduca sexta, HCLB channels in the flight sensory-motor have been shown to be involved in olfactory processing circuit. Studies show that HCLB channels are more sensitive to agonists when compared with HCLA channels, but insensitive to known LGCC insecticides. Pssm-ID: 349793 Cd Length: 185 Bit Score: 44.91 E-value: 2.21e-05
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