TRP Channels and Axon Pathfinding

Kai Cui; Xiao-bing Yuan

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Liedtke WB, Heller S, editors. TRP Ion Channel Function in Sensory Transduction and Cellular Signaling Cascades. Boca Raton (FL): CRC Press/Taylor & Francis; 2007.

TRP Ion Channel Function in Sensory Transduction and Cellular Signaling Cascades.

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Chapter 4TRP Channels and Axon Pathfinding

Kai Cui and Xiao-bing Yuan.

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Abstract

Transient receptor potential channels (TRP) are a large family of cationic channels that are permeable to Ca²⁺allowing these channels to participate in a wide range of physiological processes that require Ca²⁺ signaling. In recent years, TRP channels have been found to play a role in many processes in the nervous system, such as the transduction of sensory stimulation [1], neuronal cell death [2], proliferation and differentiation of neural progenitor cells [3,4], nerve growth [5], and synaptic transmission [6–9]. One interesting recent discovery shows that TRPC (canonical) channels are involved in the signal transduction of axon guidance during brain development.

OVERVIEW OF NERVE PATHFINDING

As the most complicated organ in animals, the brain is composed of highly ordered cell architecture and precisely wired neural circuits, which are essential for the sophisticated functions of the brain. The development of functional neuronal circuits requires the finely tuned growth of nerve fibers toward their targets, a process called nerve pathfinding [10]. Both the axon and dendrites of neurons have the pathfinding process during development, and some mechanisms were shared by these two different neuronal processes [11,12]. Therefore, in this chapter when we talk about the nerve growth or nerve guidance, we do not discuss these two processes separately without special mention. At the tip of growing nerves there is a highly dynamic structure called a growth cone, which bears motile filopodia and lamellipodia, exploring the environment and leading the nerve growth toward its favorite direction. During brain development, it is generally believed that concentration gradients of the guidance cues exist in the tissue [13,14]. When the growth cone is exposed to a concentration gradient of a chemoattractant or chemorepellent, it responds by turning toward or away from the source of the guidance cue, one of the basic behaviors of growth cones during nerve pathfinding. During this response, receptors on the growth cone’s surface can read the concentration gradient and transduce the direction signal into the cytosol, initiating a series of downstream events, including the rearrangement of the actin and microtubule cytoskeletons inside the cell [15], the changing of adhesion level at different sides of the growth cone [16], polarized endocytosis and exocytosis of vesicles containing membrane proteins, synthesis and insertion of some new proteins for nerve pathfinding [17–19], and degradation of some proteins to control the local protein level [20]. Transduction of some long-range signals back to the soma and other neurites in the same cell may be also required for the neuron to coordinate the response of different neurites in response to the stimuli [21–23]. Eventually, the growth cone will turn and grow stably in the new direction.

CALCIUM SIGNAL IN GROWTH CONE TURNING

With regard to the complicated signal transduction process during this growth cone turning triggered by guidance cues, one fundamental question is what kind of intracellular signal can be activated to mediate the directional information after the growth cone reads the concentration gradient of extracellular guidance cues. The most attractive candidate for this mediator of the growth cone guidance signal is the intracellular Ca²⁺ ([Ca²⁺]_i) [24], which regulates the motility of the growth cone and the response of growth cones to many extracellular factors [25–27]. Using an in vitro growth cone guidance model [28], previous studies showed that many extracellular factors that can guide the nerve growth, including netrin-1, slit, brain-derived neurotrophic factor (BDNF), myelin-associated glycoprotein (MAG), SDF-1, and several neurotranmitters [22,29–33], can elevate the [Ca²⁺]_i in the growth cone. Preventing the [Ca²⁺]_i elevation in growth cones by removing the extracellular Ca²⁺ (for some factors), by depleting the intracellular Ca²⁺ store, or by blocking the Ca²⁺ release from internal stores, inhibits the growth cone turning triggered by a concentration gradient of guidance cues [24]. A gradient of [Ca²⁺]_i at the growth cone is also sufficient to drive the nerve growth cone turning because an artificially generated concentration gradient of [Ca²⁺]_i, either by local photolysis of caged compound of Ca²⁺ or by an extracellular gradient of ryanodine (a drug that opens the internal store of Ca²⁺), can trigger the growth cone to extend toward the higher [Ca²⁺]_i side [29,34]. Moreover, Ca²⁺ has been shown to regulate a wide range of intracellular signaling molecules involved in nerve growth, including those microtubule- and actin-associated proteins, motor proteins, kinases, phosphotases, and proteases [24]. Based on these facts, a hypothesis is widely accepted that a concentration gradient of extracellular guidance factors can be translated into a concentration gradient of [Ca²⁺]_i across the growth cone, which then drives the preferential growth of the nerve toward the higher [Ca²⁺]_i side.

Under such a hypothesis, it is of great interest to know how the Ca²⁺ signal is triggered by guidance factors. Elevation of [Ca²⁺]_i can result from Ca²⁺ influx through voltage-gated Ca²⁺ channels in plasma membrane in response to membrane depolarization or from the opening of ligand-gated Ca²⁺ channels, for example, ionotropic glutamate receptors. Internal release of Ca²⁺ triggered by the messenger molecule inositol-1,4,5-trisphosphate (InsP3) or by Ca²⁺ itself may also contribute to elevation of [Ca²⁺]_i [24]. Another important pathway that can lead to the elevation of [Ca²⁺]_i is the Ca²⁺ influx through the voltage-independent channels including the TRP channels, which may be gated by both receptor activation and store-operated mechanisms [1,35].

Previous studies showed that both the Ca²⁺ influx through membrane channels and the Ca²⁺ release from internal stores are required for the growth cone turning triggered by a group of guidance molecules including netrin, BDNF, and MAG [13,29,30,36]. In these studies, it was shown that netrin triggers the opening of the L-type Ca²⁺ channel, an ion channel that is opened upon membrane depolarization, and Ca²⁺ influx through this voltage-gated Ca²⁺ channel is required for the attractive growth cone turning triggered by netrin [29,37]. Observations from a lot of other researchers also showed that during early development spontaneous neuronal activity is required for the proper growth and nerve pathfinding through elevating the [Ca²⁺]_i [30,38,39]. One unavoidable question raised by these studies is how could membrane potential be elevated during pathfinding of these immature neurons? This puzzle obtained an attractive answer by the exciting recent discovery that TRPC channels, whose openings are not voltage dependent, play essential roles in the axon pathfinding.

TRPCS’ FUNCTION IN NERVE GUIDANCE

TRPC5 Regulates Nerve Growth

The first clue comes from the neurite extension study carried out in cultured hippocampal neurons [5]. In order to address the function of TRPC5 channels that are expressed at high levels in the hippocampus, the dominant negative mutant proteins of TRPC5 were expressed in cultured hippocampal neurons. One interesting finding is that overexpression of wide-type TRPC5 in these neurons dramatically reduced the neurite extension rate. On the contrary, expression of dominant negative TRPC5 resulted in increased filopodia length and an elevated neurite extension rate. Consistently, a substantial amount of TRPC5 protein can be detected at the growth cone probed with a specific anti-TRPC5 antibody. The researchers concluded from these observations that spontaneous opening of TRPC5 may mediate the influx of Ca²⁺ from extracellular media, which may be adverse for the neurite extension. Since the TRPC5 channel regulates the growth cone morphology and the neurite extension rate, it is highly possible that these Ca²⁺-permeable channels may be involved in the growth cone pathfinding, which is the neurite extension controlled by extracellular factors.

TRPC Contributes to Nerve Pathfinding

New findings verified this prediction. Three independent studies showed that TRPC channels may be involved in the attractive growth cone turning triggered by the chemoattractant netrin or BDNF in cultured cerebellar granule cells of rat and embryonic spinal neurons of Xenopus [40–42]. In these studies, growth cone turning assay was used to test the response of the growth cone to an extracellular gradient of guidance factors [16,28]. A micropipette containing guidance molecules at a very high dosage was used to generate a concentration gradient of the molecule through repetitive puffing, and the gradient source (the pipette tip) was positioned 100 μm in front of the growth cone at an angle of 45 degrees with respect to the original direction of the nerve extension. The growth cone can sense this concentration gradient of guidance molecules and migrate toward or away from the gradient, depending on what guidance molecules are tested. Interestingly, all these studies showed that chemoattraction triggered by BDNF and netrin was blocked by inhibiting TRP channels with a general inhibitor SKF-96365 or by specific knocking down of the expression of endogenous TRPC protein with small interference RNA (siRNA) or morpholino-antisense RNA. Meanwhile, the [Ca²⁺]_i elevation triggered by netrin and BDNF at the growth cone was also dramatically reduced after perturbing the TRPC channels, as revealed by Ca²⁺ imaging or patch-clamp recording at the growth cone. This suggests that in response to the stimulation of BDNF and netrin, TRPC channels may mediate the Ca²⁺ influx, which is required for triggering the growth cone turning. Moreover, the cation influx through TRP channels may elevate the level of membrane potential, leading to the activation of a voltage-dependent sodium channel and calcium channels, which further depolarize membrane potential and allow more Ca²⁺ influx. These studies also showed that the role of TRPC channels in growth cone turning is specific. In rat granule neurons, TRPC3 and 6 are only required for BDNF-triggered growth cone attraction but not for either growth cone attraction triggered by glutamate or repulsion triggered by SDF-1. In the Xenopus spinal neurons, the chemoattractant netrin and BDNF as well as the repellent MAG engage Xenopus TRP-1 (xTRPC1) to guide the growth cone, while another guidance molecule (semaphorin) doesn’t use it [42].

The requirement of TRPC channels in the axon guidance in vivo was further demonstrated by Shim et al. [42] Apart from a similar observation using the growth cone turning assay, they looked at the growth of the commissural axons in the spinal cord after injection of the morphalino RNA of the xTRPC1 in one cell at the two-cell stage of the embryo to silence the expression of xTRPC1 proteins during development. They found that knocking down the expression of xTRPC1 dramatically deferred the midline cross of these commissural axons and caused some axons to go astray, suggesting that the xTRPC1 channel can mediate the axon guidance signal in vivo. Although currently no TRPC knockout mice have been reported to have nerve pathfinding defects, it may be due to the compensation of protein function by other TRP family members when a single TRPC gene is knocked out. It is possible that defects in nerve pathfinding may be seen in mice of compound knockout of several family members.

Not only chemoattraction requires TRPC channels, it was also shown that the repulsive growth cone turning triggered by MAG was also eliminated by blocking the xTRPC channels [42]. Because MAG is one of the molecules that prevents axon regeneration after the injury of central nervous systems in adult animals, the engagement of the TRPC channel in MAG signaling suggests that these ion channels will be candidate drug targets to enhance nerve regeneration.

TRPC Gating Mechanisms by Guidance Factors

One study explored the opening mechanism of the TRPC channel in the growth cone by the guidance molecule BDNF [40]. Similar to the PLC dependency of many other TRP channels, the researchers found that both the growth cone attraction and the elevation of [Ca²⁺]_i triggered by BDNF were blocked by inhibition of PLC signaling with the specific inhibitor U73122. In contrast, inhibition of PKC activity did not have any effect. Furthermore, blocking the InsP3 signaling with xestospongin C or 2APB, which perturb the InsP3 receptor at the internal store of Ca²⁺, also blocked the growth cone turning and [Ca²⁺]_i elevation, suggesting that Ca²⁺ release from internal stores may be required for the opening of TRPC channels in the plasma membrane. Overall, these observations support such a model where the binding of BDNF with its receptor TrkB activates PLC-γ, which generates IP₃ [43] (see Figure 4.1). The subsequent opening of IP₃ induces the Ca²⁺ release from internal stores. This Ca²⁺ elevation can further activate the TRPC channels in the plasma membrane and allow more Ca²⁺ influx. In such a model, TRPC channels in the growth cone membrane should be activated through some Ca²⁺-dependent mechanisms (Figure 4.1). This was supported by the recent report that the activation of TRPC5 by agonists can be regulated by calmodulin and [Ca²⁺]_i [44]. Because many extracellular factors that have been shown to regulate nerve growth can activate PLC activity through receptor tyrosine kinase or G-protein-coupled receptors that are linked to the signaling of PLC-γ and PLC-β, respectively [45,46], PLC-dependent TRP channel activation may also mediate Ca²⁺ signaling for other guidance factors during nerve pathfinding. However, how the activation of guidance receptors is coupled to the opening of TRPC channels, and whether there is direct association of guidance receptors with the TRPC protein like the binding of TrkB with TRPC3 [47], remains to be clarified.

FIGURE 4.1

TRPC channels in nerve guidance. An extracellular gradient of guidance cue (from left upper corner) triggers local [Ca²⁺]_i elevation, establishing a [Ca²⁺]_i gradient across the growth cone. The graded calcium signal causes imbalanced polymerization/stablization (more...)

How TRPC Channels Contribute to Guidance Signaling

Among various TRPC proteins, TRPC3, TRPC6, and TRPC7 belong to one subfamily [35,48] and can form functional heteromeric or homomeric ion channels [49,50]. In cultured hippocampal neurons, expression of DN-TRPC5 elevates neurite extension, whereas overexpression of wild-type TRPC5 inhibits nerve growth [5]. However, down-regulation of TRPC3/6 did not significantly affect neurite growth in cerebellar granule cells [40]. This differential effect on nerve growth may owe to longer mean channel open time of TRPC5-containing channels than TRPC3/6 channels. That allows much larger Ca²⁺ influx [51–53], leading to adverse effects to neurite growth, whereas a modest level of Ca²⁺ influx through a TRPC3/6 channel is sufficient to trigger attractive growth cone turning. By allowing different patterns of Ca²⁺ influx, diverse TRPC channels may thus carry out distinct regulatory functions at the growth cone.

Previous studies have divided the guidance molecules in two groups depending on the requirement of extracellular Ca²⁺ and the modulation properties by cyclic AMP (cAMP) or cyclic GMP (cGMP) during the growth cone turning triggered by these factors [13]. Type I factors require the extracellular Ca²⁺ to trigger the growth cone turning, and cAMP level can switch the turning response of the growth cone, with a higher level of cAMP leading to chemoattraction and a lower level to repulsion. In contrast, the growth cone turning triggered by type II guidance molecules is independent of extracellular Ca²⁺ and is switched by intracellular cGMP level. Intracellular calcium signaling (with either type I or II factors) is required for the growth cone turning response [13]. It is possible that TRP channels participate in the growth cone guidance triggered by type I factors, by which the Ca²⁺ release from internal stores is not sufficient to trigger the growth cone turning. For the type II factors, however, the Ca²⁺ release from internal stores upon receptor activation may be enough to drive the turning responses. Meanwhile, the opening of ryanodine channels at the internal stores also contributes to the Ca²⁺ signaling in netrin-triggered chemoattraction [29].

For the type I guidance factors, TRPC channels may not necessarily be the sole membrane ion channels engaged in the nerve pathfinding. The opening of these cationic channels allows the depolarization of membrane potential in response to the stimulation of guidance molecules. In consequence, voltage-gated cationic channels will open and trigger the further depolarization of the membrane potential, accompanied with influx of Ca²⁺ through voltage-dependent calcium channels [41]. Calcium-triggered Ca²⁺ release from internal stores may also be triggered as a consequence of [Ca²⁺]_i elevation. Calcium from all these sources may contribute to nerve growth and nerve pathfinding in some neuronal tissues; however, TRPC activation is the trigger of signal amplification in response to type I guidance factors.

POSSIBLE ROLES OF TRP CHANNELS IN NEURONAL MIGRATION

Calcium Signal in Neuronal Migration

Apart from nerve pathfinding, other processes in neural development may also be regulated by TRP channels. One such developmental process is neuronal migration. Unlike nerve growth, neuronal migration is the translocation of the whole cell body including the leading process and the soma. However, some signaling processes may be shared by both nerve pathfinding and neuronal migration. One example is that a series of guidance factors—slit, netrin, ephrins, BDNF, SDF—have been shown to be used for both nerve guidance and the guidance of neuronal migration [54]. Moreover, the Ca²⁺ signal has been shown to regulate the speed and direction of neuronal migration [55–58]. One example is the neuronal migration in postnatal cerebellum tissue, in which a high frequency of Ca²⁺ waves is correlated with the high migrating speed of the young granule cells [55], and the end of the Ca²⁺ wave is linked to the cease of the migration [58]. NMDA receptor activity and N-type Ca²⁺ channels are required to maintain the normal migration of these neurons [59]. Therefore, it is highly possible that TRPC channels that participate in the nerve guidance signaling, and whose openings allow Ca²⁺ influx into the cytosol, may also play a role in controlling the motility and the guidance of neuronal migration. Determining which TRPC proteins are involved in neuronal migration deserves further study.

Mechanosensation in Migrating Neurons?

During its migration, stress and tension are generated toward the neuron because it has to attach and squeeze in surrounding tissue, which is filled with other cells and an extracellular matrix. The same is true for the exploring growth cone, although the size of the growth cone is relatively smaller. These mechanical forces and their change over time may reflect current motility and position of the migrating cell. It is likely that cells sense and use this information to fine-tune their pace and direction of migration, such as changing their shapes in order to select a way of stronger adhesion and lower resistance to their movements. Consistent with this possibility, it was frequently observed that neurons change their shapes dramatically during migration including becoming highly elongated [60,61]. Therefore, it is reasonable to hypothesize that mechanical sensing may play an important role in neuronal migration, helping the neuron to actively reorganize the cytoskeleton, to change its shape, or even to reduce and recover its volume in order to fight its way in tissues. In agreement with this prediction, mechanically stimulated currents were recorded in the growth cones of cultured snail neurons and rat DRG neurons [62,63]. More interestingly, filopodia, which play an essential role in exploring the surrounding tissue, were the most sensitive to mechanical stimulation. Mechanical tension can be an important regulator of nerve growth because neurite outgrowth can be initiated de novo by experimental application of tension to the cell margin of neurons in culture prior to spontaneous neurite outgrowth [64–66]. The “towed” neurites had a normal appearance, showed rapid saltatory movements of internal organelles, and were capable of sustained growth on the substratum. Electron microscopy of bundles of neurites produced in this way from explanted dorsal root ganglia showed an ultrastructure typical of cultured neurites, with abundant longitudinally aligned microtubules and neurofilaments [64,67]. In cultured hippocampal neurons, applied mechanical tension could stimulate undifferentiated minor processes to become axons and could induce a second axon in an already polarized neuron [68]. In a cultured fibroblast, it was reported that stretch-activated Ca²⁺ entry sustains cell migration and mediates active and passive responses to mechanical signals [69]. In this study, application of gadolinium, an inhibitor of stretch-activated ion channels, or removal of extracellular-free Ca²⁺, caused inhibition of traction forces. Gadolinium treatment also inhibited cell migration [69]. Immunofluorescence microscopy indicated that gadolinium caused a dramatic decrease in vinculin and phosphotyrosine concentrations at focal adhesions, suggesting that stretch-activated Ca²⁺ entry regulates the organization of focal adhesions and the output of mechanical forces. Likewise, mechanosensory channels may be involved in the migration of neurons during development.

So far, the molecular nature for these mechanical sensors at the migrating growth cone and soma remains unknown. Some researchers reported that the N-type calcium channel on the cell membrane is mechanosensitive [70]. Interestingly, N-type calcium channels have been reported to play a role in directed migration of immature neurons as indicated by the reductive effect of the channel’s inhibitor on the migration of cultured cerebellar granule cells [71]. In contrast, inhibitors of L- and T-type calcium channels, as well as those of sodium and potassium channels, had no effect on the rate of granule cell migration [71]. Because gadolinium, a drug previously used to inhibit stretch-activated ion channels, can also block or activate TRP channels at different concentrations [72], it is unclear whether this drug reduced the migration of fibroblasts [69] through inhibiting TRP channels. The recent discovery that TRP channels play essential roles in mechanical sensing in sensory neurons [1,73] raised the possibility that these TRP channels may play a role in sensing the adhesion and compactness of the surrounding tissue of migrating neurons. Whether the mechanosensitive TRP channels in sensory neurons are also expressed in migrating neurons during development and whether they really serve as the mechanical sensor and influence neuronal migration will be fascinating subjects for further investigation.

Thermosensation for Migration?

Imaging studies in brain slice cultures showed that neuronal migration is highly sensitive to temperature [59,60,74]. Considering that TRP channels play essential roles in heat and cold sensing [1,35] and that some of these TRP channels are also expressed in the brain [35,75], one reasonable supposition is that these channels also sense temperature when the neurons migrate in a normal tissue environment, allowing Ca²⁺influx and maintaining a suitable level of Ca²⁺ in the cytosol to keep the motility of the cells. Exploring the expression patterns of TRP family members in the brain at different developmental stages will help to determine which TRP proteins may be actively involved in specific developmental processes.

CONCLUSION

Evidence is emerging that Ca²⁺-permeable TRP channels regulate nerve growth and pathfinding. The Ca²⁺ permeability and various gating mechanisms suggest that TRP channels may be widely involved in other developmental processes including neuronal migration, dendrite arborization, spine generation, and synapse formation. How TRP channels are opened by various physiological stimuli during development remains unclear. The next several years will witness the identification of more functions played by TRP channels in various developmental processes. The further clarification of the function of TRP channels and the underlying mechanisms in neural development will dramatically increase our understanding of how brain circuits are connected.

ACKNOWLEDGMENTS

We would like to thank Dr. Yi-zheng Wang, Ning Li, and Chen-bing Guan for comments on the manuscript.

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Cui K, Yuan X. TRP Channels and Axon Pathfinding. In: Liedtke WB, Heller S, editors. TRP Ion Channel Function in Sensory Transduction and Cellular Signaling Cascades. Boca Raton (FL): CRC Press/Taylor & Francis; 2007. Chapter 4.

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Abstract
OVERVIEW OF NERVE PATHFINDING
CALCIUM SIGNAL IN GROWTH CONE TURNING
TRPCS’ FUNCTION IN NERVE GUIDANCE
POSSIBLE ROLES OF TRP CHANNELS IN NEURONAL MIGRATION
CONCLUSION
ACKNOWLEDGMENTS
REFERENCES

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