Abstract

In the pair of the nematode Caenorhabiditis elegans serotonergic chemosensory neurons ADF, the TRPV channel protein OCR-2 interacts with another TRPV protein, OSM-9, to control the production of the neurotransmitter serotonin. The activity and specificity of OCR-2 in the serotonergic neurons is governed by structural determinants within the channel protein in concert with defined cellular components. The dynamic gating mechanisms, multiple sensory modalities, and functional conservation in diverse organisms make TRPV channels ideal candidates for the long-awaited molecular sensors that underscore the ancient role of the serotonergic system in coupling sensory cues and internal milieu to behavior and physiology.

INTRODUCTION

The serotonergic system is an ancient sensor of diverse stimuli. Serotonin (5-hydroxytryptamine; 5-HT) is a monoamine and functions as a neuromodulator participating in the elaboration of adaptive responses to external stimuli and physiological challenges. The first demonstration of serotonin in regulating sensory response was from studies in Aplysia, where increased serotonin promotes sensitization of the gill-withdrawal reflex in response to repetitive tactile stimulus to the mantle or the edge of the siphon (Brunelli et al., 1976; Bailey et al., 1992). Although a serotonin signal is produced from the interneurons rather than from the sensory neurons in the gill-withdrawal reflex circuitry (Kandel and Schwartz, 1982), this showed that the activity of a specific set of serotonergic neurons is modulated by a specific external cue to influence behavior. Anatomic analysis of the serotonergic system in mammalian CNS revealed their close relationship to blood vessels, leading to the proposal that the raphe serotonergic neurons may directly function as chemoreceptors and mech-anoreceptors to transduce diverse neuronal and nonneuronal signals into discrete behavior and physiological processes (Scheibel et al., 1975; Azmitia, 1999). Consistent with this notion, application of distinct chemical and physical stimuli to whole organisms or brain slices induces up- and downregulation of serotonin synthesis in discrete serotonergic neurons in the CNS (Boadle-Biber, 1993; Leibowitz and Alexander, 1998; Azmitia, 1999; Chaouloff et al., 1999; Adell et al., 2002).

If serotonergic neurons can discriminate ligands or cues that reflect external stimuli and internal milieu, molecular biology predicts that different serotonergic neurons express different receptors. Two such cell-specific regulators have been identified in C. elegans: the TRPV (vanilloid subfamily of transient receptor potential) channel proteins OCR-2 and OSM-9. This chapter highlights the conservation of the serotonergic system in C. elegans, describes the role of OCR-2 and OSM-9 in the serotonergic neurons, explains how these two TRPV channel proteins can be activated by multiple sensory stimuli but maintain specificity to each modality, and, finally, discusses the possibility of serotonin as a conserved readout of TRP channel signaling.

CONSERVATION OF THE SEROTONERGIC SYSTEM IN C. ELEGANS

As in all animals, serotonergic neurons represent a small population in C. elegans. A mature hermaphroditic worm has exactly 302 neurons (White et al., 1986). The nine neurons that can be stained by an antibody raised against serotonin are composed of five neural classes, with four classes consisting of two bilaterally symmetric neurons (Horvitz et al., 1982; Sze et al., 2000). C. elegans does not have a defined CNS; nevertheless, the serotonergic neurons are connected to the central neuronal integration center called the nerve ring (White et al., 1986) and influence sensory behavior, both innate and learned, and diverse physiological processes (for examples, see Weinshenker et al., 1995; Colbert and Bargmann, 1997; Nurrish et al., 1999; Sze et al., 2000; Sawin et al., 2000; Zhang et al., 2005). ADF are the only serotonergic sensory neurons in the animal. The sensory cilia of ADF are exposed to the external environment (White et al., 1986) and sense salts (Bargmann and Horvitz, 1991; Hukema et al., 2006). A recent study showed that serotonin produced from ADF mediates olfactory learning (Zhang et al., 2005). NSM are secretory neurons with their cell bodies located in the pharynx and are likely sensing signals released from food (Sawin et al., 2000). HSN are motor neurons that couple feeding status and the rhythm of vulva muscle contractions to release fertilized eggs (Desai et al., 1988). RIH and AIM are interneurons, bridging between sensory inputs and command outputs (White et al., 1986). The unique, distinguishable function of the serotonergic neurons in C. elegans provides a genetic tractable model to investigate the genes that regulate serotonergic phenotypes in identified neural types.

Classic mutant screens in conjunction with gene knockout technology have led to the isolation of mutant animals with deficits in serotonin biosynthesis, serotonin release, and serotonin receptors (Duerr et al., 1999; Sze et al., 2000; Ranganathan et al., 2000; Hare and Loer, 2004; Dempsey et al., 2005). Genes used to produce serotonergic phenotypes are highly conserved between worms and humans. Three of those—tph-1, cat-1, and mod-5—are relevant here. The tph-1 gene encodes the tryptophan hydroxylase that catalyzes the rate-limiting first step of serotonin biosynthesis, and the tph-1 deletion mutant has no detectable serotonin (Sze et al., 2000). Like in mammals, signaling by serotonin in C. elegans involves two distinct mechanisms of serotonin transporter. cat-1 encodes the vesicular monoamine transporter (VMAT) on the secretory vesicles that pump newly synthesized serotonin into vesicles for regulated exocytosis (Duerr et al., 1999), and mod-5 encodes the membrane serotonin transporter (SERT) for reuptake of extracellular serotonin (Ranganathan et al., 2001). SERT is the target of two major classes of antidepressants: selective serotonin reuptake inhibitors (SSRIs) and tricyclic drugs. It is generally assumed that these drugs exert therapeutic effects by blocking SERT from reuptaking serotonin, thereby increasing the availability of serotonin at the synapse (Blier and de Montigny, 1998). A recent study in our laboratory found that worms either bearing a deletion in the SERT gene mod-5, or wild-type worms treated with the SSRI fluoxetine, accumulate serotonin only in the ADF, NSM, and HSN neurons (C. Dempsey and J. Sze, unpublished). This indicates that two classes of the serotonergic neurons in the head (AIM and RIH) can only absorb extracellular serotonin via MOD-5/SERT and that fluoxetine blocks MOD-5 activity. Such serotonin-absorbing neurons have also been observed in developing rat embryos throughout sensory pathways from the CNS to sensory neurons (Hansson et al., 1998; Lebrand et al., 1998), and in the hypothalamic dorsomedial nucleus in postnatal life (Hoffman et al., 1998). In worms as well as in mammals, these neurons do not express the complete set of serotonin synthesis enzymes, but they do express VMAT. One possible function for these neurons could be serving as “relay stations” that pass serotonin from originating neuron sources to specific serotonin receptor subtypes on distant targets. The potential effects of the blockage of SERT by SSRIs and tricyclic drugs in the pathways mediated by these neurons are fascinating but beyond the scope of this chapter. What is relevant is the conservation of the mechanisms of serotonin neurotransmission and of the principle action of the SSRIs on SERT in the worm, which gives a more concrete reason to use the C. elegans serotonergic system as a model for understanding the fundamental mechanisms that regulate serotonin signaling.

THE FUNCTION AND MECHANISM OF OCR-2 AND OSM-9 IN SEROTONERGIC NEURONS

A role of TRPV channels in serotonin signaling was identified from an unbiased genetic screen for serotonin synthesis mutants (Zhang et al., 2004). Because tryptophan hydroxylase is the key enzyme for serotonin synthesis, and the expression of GFP tagged the tph-1 gene (tph-1::gfp), which can be unambiguously identified and, to some extent, quantified in specific serotonergic neurons of living worms, a goal of this screen was to ask whether tph-1 expression in different classes of neurons is regulated by different genes. It turned out most mutants retrieved from the screen were missing tph-1::gfp expression specifically in one class of the serotonergic neurons. The first two genes identified that regulate tph-1 expression in the ADF chemosensory neurons are the TRPV genes osm-9 and ocr-2. Null mutations in either osm-9 or ocr-2 dramatically downregulate tph-1::gfp expression in the ADF neurons, but tph-1::gfp expression in the NSM and HSN neurons is unaffected in the mutants. And there is no detectable difference in the intensity of tph-1::gfp expression between double mutants of ocr-2 and osm-9 with each of the single mutants.

Several lines of evidence indicate that both OCR-2 and OSM-9 act in the ADF neurons to regulate serotonin production. OCR-2 and OSM-9 are coexpressed in ADF (Tobin et al., 2002; Zhang et al., 2004). By expressing wild-type ocr-2 or osm-9 coding sequences under cell-specific promoters, it was demonstrated that expression of OCR-2 and OSM-9 in ADF is necessary and sufficient to restore tph-1 expression in respective mutants. These findings are consistent with earlier evidence that OCR-2 and OSM-9 require each other for routing to the sensory cilia of the neurons (Tobin et al., 2002), suggesting an OCR-2 and OSM-9 protein complex at the sensory cilia of ADF that regulate tph-1 expression. For the rest of this chapter, the term OCR-2/OSM-9 will be used when they are considered as one complex.

Does OCR-2/OSM-9 represent a molecular sensor that couples sensory cues to serotonin signaling? To address this question, it is important to consider how specific tph-1 downregulation is in the mutants. Biophysical characterization of OCR-2 and OSM-9 in a heterologous expression system has not been successful, but TRP channels are generally considered as calcium-permeable cation channels (Montell, 2005; Pedersen et al., 2005; Ramsey et al., 2006). Disruption of cellular calcium homeostasis can affect a battery of cellular events, even causing cell death (Berridge et al., 2003). However, ocr-2 and osm-9 mutations do not appear to cause cell-fate transformation. In addition to ADF, OSM-9 and OCR-2 are coexpressed in five pairs of nonserotonergic chemosensory neurons: AWA, ADL, ASH in the head, and PHA and PHB in the tail (Tobin et al., 2002). Mutations in osm-9 and ocr-2 do not cause these neurons to degenerate or to exhibit a morphological change detectable at the level of fluorescence microscopy (Colbert et al., 1997; Zhang et al., 2004). Null mutations in osm-9 and ocr-2 also do not reduce the expression of every gene in ADF. In fact, all the ADF neuronal markers that have been examined showed no distinguishable difference between mutants and wild-type animals, including the expression of the cat-1/VMAT gene and the cat-4 gene that encodes the tryptophan hydroxylase cofactor GTP-cyclohydrolase I (Zhang et al., 2004). These findings suggest that the signaling from OCR-2/OSM-9 selectively, if not specifically, regulates tph-1 expression. An attractive model is that the TRPV channel is regulated by environmental signals to in turn regulate serotonin signaling by transcriptional regulation of the key serotonin synthetic enzyme tryptophan hydroxylase.

Characterization of OCR-2/OSM-9 function in other chemosensory neurons provides some consensus why tph-1 is a selected target of the channel in the ADF neurons. ocr-2 and osm-9 mutants also are defective in olfactory sensation to the odorant diacetyl. Diacetyl is sensed by the G-protein-coupled receptor ODR-10, which is expressed specifically in the AWA neurons (Sengupta et al., 1996). odr-10 expression but not several other AWA markers is reduced in ocr-2 and osm-9 mutants (Colbert et al., 1997; Tobin et al., 2002). It seems that OCR-2/OSM-9 signaling regulates the expression of genes unique for sensory detection and sensory output of the particular cell. Such activity-dependent transcriptional regulation of sensory components may endow the TRPV channel to regulate the sensitivity to sensory stimuli and underscore the mechanisms of serotonin signaling in modulating behavior based on the sensory experience.

SPECIFICITY OF OCR-2 AND OSM-9 SIGNALING PATHWAYS IN DIFFERENT SENSORY NEURONS

OCR-2 and OSM-9 are colocalized in the sensory cilia and plasma membrane of four pairs of chemosensory neurons: ADF, AWA, ASH, and ADL. The sensory cues and activation mechanisms of OCR-2/OSM-9 in ADF are not yet determined. Nevertheless, genetic analyses of OCR-2 and OSM-9 in individual sensory neuron functions and their functional interactions with other components in the sensory signaling pathways have produced some basic ideas for understanding and further deducing how the same channel entity mediates multiple sensory modalities but remains faithful to each sensory function in vivo (Figure 18.1).

FIGURE 18.1

Polymodality and specificity of OCR-2/OSM-9 in vivo. (A) OCR-2/OSM-9 in different sensory functions are regulated by distinct mechanisms. OCR-2 and OSM-9 likely form a heteromeric channel and are located in the sensory cilia and plasma membrane of four (more...)

TRP CHANNELS IN MAMMALIAN SEROTONERGIC SYSTEMS?

Identification of OCR-2/OSM-9 as a regulator of serotonin production in C. elegans raises the question of whether TRP channels also function in mammalian serotonergic systems. There is not yet explicit evidence indicating that any mammalian TRPV protein is expressed in serotonergic neurons. However, there is compelling evidence that TRPV1–V5 are expressed broadly in the CNS, including the hippocampus, amygdala, and hypothalamus (Xu et al., 2002; Smith et al., 2002; Vennekens et al., 2002). These brain areas receive rich serotonergic innervation and are the commanders for sensory-endocrine integration, emotion, and cognitive functions. TRPV1 and V4 act as molecular sensors in vivo, and TRPV1–V4 are each activated by diverse chemical and physical stimuli in heterologous expression systems (Ramsey et al., 2006). Interestingly, intranigral injection of the TRPV1 ligand depleted serotonin level in the nigra (Dawbarn et al., 1981). Also, peripherally administered capsaicin resulted in changes in the electroencephalogram activity in the dorsal raphe, the area enriched with serotonergic nuclei (Rabe et al., 1980), and TRPV4 is a locus associated with bipolar affective disorders (Delany et al., 2001). These studies do not establish the TRPV1 and TRPV4 regulating serotonin signaling but they imply that TRPV channels play a broad role through their functions in the CNS and probably via the serotonergic system.

Multiple sensory modalities, diverse gating mechanisms, and associations to distinct signaling cascades of OCR-2/OSM-9 provide insights into how a single channel entity can be dedicated to multiple sensory functions in vivo. The five mammalian TRPV channel genes expressed in the brain can produce a vast array of distinct channels through splicing variants, heteromeric combinations, and associations with distinct cellular components. These properties endow TRP channels to serve as molecular sensors in billions of years of metazoan evolution. It is tempting to speculate that these ancient molecular sensors and the ancient cellular censors, the serotonergic neurons, co-evolved. Like in C. elegans, TRP channels may function in a small subset of the serotonergic neurons in mammals. Alternatively, myriad diverse channels may underscore distinct serotonergic neurons in a wide spectrum of sensory functions. Even brain serotonergic neurons are not directly exposed to the external environment like the ADF neurons in C. elegans, but they may still sense chemical ligands and physical stimuli from other neuronal and nonneuronal cells and from the vesicular systems (Scheibel et al., 1975), therefore linking the gating information of TRP channels, sensory stimuli, serotonin production, and its downstream signaling.

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