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Zhu MX, editor. TRP Channels. Boca Raton (FL): CRC Press/Taylor & Francis; 2011.

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TRP Channels.

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Chapter 10TRPC Channels in Neuronal Survival

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The family of transient receptor potential canonical (TRPC) proteins was the first group of TRP homologs cloned in mammals1 after discovery of the TRP protein in Drosophila.2 There are seven members in this family (TRPC1–7). The TRPC channels formed by homo- or heteromeric TRPC proteins are Ca2+-permeable nonselective cation channels. According to the similarity in amino acid sequence, the mammalian TRPCs can be classified into four subgroups: TRPC1, TRPC2, TRPC3/6/7, and TRPC4/5,3 while the TRPC2 is a pseudogene in primates.4 The TRPC proteins have six transmembrane domains, and both N- and C-termini of these proteins are intracellular, suggesting that these channels can be regulated by intra cellular signaling molecules. These channels can be activated in various cell types by G-protein-coupled receptors (GPCR) and receptor tyrosine kinases (RTK) through a phospholipase C (PLC)-dependent mechanism. Therefore, TRPC channels may act as a sensor for environmental cues.

Neuronal survival is important for brain development and for pathogenesis of certain diseases in the central nervous system (CNS). During development, groups of neurons are chosen to keep alive and to establish elaborated networks. Under pathologic conditions, such as ischemic injury and degenerative diseases, neuronal survival is compromised, leading to brain injury and psychological disorders. To promote neuronal survival, complicated processes are involved in which both neurotrophins and Ca2+ play critical roles. Because Ca2+ is known to mediate cell survival, it is possible that Ca2+ influx via TRPC channels is required for neuronal survival promoted by neurotrophins, the receptors of which are RTKs. All TRPC channels have been found in mammalian CNS. As possible modulators or integrators of various cellular signals, TRPC channels can upregulate a series of pathways for neuronal survival. Studies about the roles of TRPC channels in neuronal survival could help us to understand how neurons endure and survive in the complex situations during maturation and under insults. This review will focus on the possible roles of TRPC channels in neuronal survival.


10.2.1. Structure of TRPC Proteins

As a subfamily of TRP channels, each of the seven members of TRPCs has six transmembrane domains predicted by the amino acid sequence. There is as yet no crystal structure of any TRP channel. It is believed that their three-dimensional structures could be roughly similar to those of K+ channels.5 TRP proteins form tetrameric structures when they assemble as a channel, just like K+ channels, and recent studies of electron cryomicroscopy of TRPV1 confirm the prediction.6,7 Figure 10.1 shows the schema of a general structure of a TRPC channel protein on the plasma membrane according to the work of Vannier et al.8 Both the N- and C-termini are cytoplasmic. At the N-terminal, there are three to four ankyrin-like repeats, followed by a coiled coil region. Ankyrin-like repeats are a common protein–protein interaction domain, although there is no conserved binding partner. Several proteins have been reported to interact with this region of different TRPCs. MxA, an interferon-induced GTPase that can inhibit the multiplication of RNA viruses, has been shown to interact with the second ankyrin-like repeat domain in mammalian TRPCs, and it can regulate TRPC channel activities.9 RNF24, a membrane RING-H2 protein, was found to interact with the ankyrin-like repeat domain of TRPC6 and colocalize with TRPC3.10 This protein is thought to affect trafficking of TRPC proteins in the Golgi apparatus.10 Moreover, these repeat domains have been recently found necessary for the assembly of TRPC4 and TRPC5,11 while only the coiled coil region was shown to contribute to the homo- and heteromeric TRPC channel formation previously.12 This function of the coiled coil region is plausible because this protein motif is commonly used to control oligomerization.13,14 Notably, the N-terminal coiled coil regions of TRPC4 and TRPC5, but not other TRPCs, interact with stathmin, a microtubule destabilizing phosphoprotein. This interaction with stathmin may play a role in TRPC4- and TRPC5-mediated inhibition of neurite outgrowth during development.15

FIGURE 10.1. Schematic structure of TRPC proteins.


Schematic structure of TRPC proteins. 1-6: transmembrane domains of TRPC proteins. ANK: ankyrin-like repeat. CIRB: calmodulin/IP3 receptor binding region. The PDZ binding domain is specific for TRPC4 and TRPC5.

The putative pore region of TRPCs is located between the fifth and the sixth transmembrane domains. The conserved hydrophobic α-helix in this region has been confirmed by mutagenesis analysis to be important for the opening and selectivity of TRPC channels.16,17 Compared with the N-terminus, the C-terminus of TRPC proteins has been reported to interact with regulatory proteins. The EWKFAR motif, together with the proline-rich motif (LPXPFXXXPSPK) that follows it, is highly conserved in the TRPC family. This 25-amino-acid region is also termed TRP domain.3 In TRPCs, this domain has been reported to be necessary for interaction with Homer (only for TRPC118 and possibly for TRPC319) and immunophilin.20 After the TRP domain, a calmodulin (CaM)/inositol 1,4,5-trisphosphate (IP3) receptor binding (CIRB) region has been identified in all TRPC proteins,21 while TRPC1 and TRPC5 have an additional CaM binding site downstream of CIRB.22,23 An extended region, including a PDZ binding domain, is found in TRPC4 and TRPC5 at the end of the C-terminus. This domain is responsible for TRPC interaction with the Na+/H+ exchanger regulatory factor (NHERF). This interaction likely enables TRPC4 and TRPC5 to form signaling complexes with PLCβ and to link with the actin cytoskeleton.24,25

10.2.2. Activation and Regulation

It has been proposed that TRPC channels are involved in the processes of storeoperated Ca2+ entry (SOCE) and receptor-operated Ca2+ entry (ROCE).26,27 SOCE, also termed store depletion-activated Ca2+ entry, describes Ca2+ influx following the depletion of intracellular Ca2+ stores. ROCE refers to Ca2+ influx triggered by PLC activation when GPCR or RTK pathways are stimulated. Activated PLCs cleave phosphatidylinositol 4, 5-bisphosphate (PIP2) to generate diacylglycerol (DAG) and IP3, and ROCE can be enhanced by IP3-induced intracellular Ca2+ store depletion. Therefore, ROCE and SOCE are different pathways with reciprocal regulation.27 All TRPC channels can be activated by stimulating PLCs,28 with either Gq-coupled pathways stimulating PLCβ or RTK signaling pathways activating PLCγ. These two signaling pathways are the typical modes for TRPC channel activation through the ROCE mechanism. There are two proposals about how TRPC channels are activated by PLCs. In one, IP3 causes Ca2+ depletion from the intracellular stores by interacting with IP3 receptors, and the Ca2+ store depletion can lead to activation of TRPC channels. In the other, DAG directly activates TRPC channels.3,28

In heterologous expression systems, TRPC channels have been reported to be activated by Ca2+ store depletion, except for TRPC6.2933 In native conditions, TRPC3 can be activated by Ca2+ store depletion.34 In rat primary pontine neurons, the native TRPC3 channel conductance (IBDNF) can be initiated by brain-derived neurotrophic factor (BDNF). The activation of IBDNF requires PLC. Also, if the Ca2+ level is elevated in the cytoplasm or IP3 receptors are blocked, IBDNF cannot be induced. Furthermore, IBDNF is not initiated by DAG,34 suggesting that the activation of the endogenous TRPC3 likely depends on Ca2+ store depletion.

DAG and its analogs can also trigger TRPC conductance in native conditions. In cultured B lymphocytes and smooth muscle cells, TRPC6 and TRPC7 can be activated by DAG, and such activation is abolished when TRPC6 and TRPC7 proteins are eliminated.35,36 TRPC3 and TRPC6 can be activated by DAG independent of Ca2+ store depletion when they are overexpressed in CHO-K1 cells.37 However, DAG can also activate PKC, which inhibits TRPC channels.38 For this reason, in DT40 B cells, TRPC7 can be activated by DAG only when PKC activity is suppressed.39 TRPC4 and TRPC5 cannot be activated by DAG.37,38

Additionally, altering the expression of TRPC proteins in the plasma membrane may also affect TRPC activation. Several in vitro studies support this proposal.4043 In HEK293 cells stably transfected with TRPC6, the level of the TRPC6 protein in the plasma membrane increased within the first 30 s of GPCR stimulation or store depletion. PLCs may also be involved in this process to regulate Ca2+ influx via TRPC channels.42 In hippocampal neurons, TRPC5 is translocated to the plasma membrane when RAC1 is activated. This process involves synthesis of PIP2 and is thought to be important in Ca2+-dependent neurite growth repression.44


The mRNA expression pattern of TRPCs in different tissues from rodents to human shows that TRPCs are highly expressed in all regions of the CNS.4547 Results of immunohistochemistry studies also confirm the expression of TRPC proteins in the CNS. In the hippocampus, TRPC1, TRPC3, TRPC4, and TRPC5 are found in the pyramidal cell bodies of CA1 or CA3 regions, as well as in the granule cell bodies of the dentate gyrus, while TRPC6 is dispersedly stained only at the molecular layer of the dentate gyrus.48 In rat substantia nigra, TRPC6 is found at the proximal dendrites and axon hillock of tyrosine hydroxylase (TH)-positive neurons, well colocalized with mGluR1, but with little signal in nuclei and presynaptic regions.49 TRPC3 has been reported to have preferential distribution in oligodendrocytes.50 TRPC4 and TRPC5 are the predominant TRPC subtypes in the adult rat brain because both are expressed highly in the frontal cortex, pyramidal cell layer of the hippocampus, and dentate gyrus.47 Comparatively, TRPC4 is specifically detected throughout layers 2–6 of the prefrontal cortex, motor cortex, and somatosensory cortex, while TRPC5 seems to be present in layers 2, 3, 5, and 6 of the prefrontal cortex and anterior cingulated.47

In brain development, the mRNA for TRPCs, except TRPC4, can be detected in the E13 mouse brain.51,52 During this period, the expression of TRPC1 is specifically detected in some post-mitotic neurons distinct from Cajal-Retzius cells at the preplate, while it overlaps with 80% of the proliferative neural stem cells in the embryonic telencephalon.51,53 TRPC3, together with TRPC6, localize to BrdU-positive cells, while TRPC6 is also found in neuronal cells.51 TRPC4 mRNA is not expressed until E14.5. It is then found prominently in the cortex, septal area, pyramidal cells of the hippocampus, granule cells of the dentate gyrus, and cerebellum. During development to adulthood, TRPC4 mRNA levels decline significantly in these brain regions except for the hippocampus.52 TRPC3 and TRPC6 are also found to have a peak of postnatal expression in the cerebellum, and their expression patterns are consistent with their important roles in neuronal survival during brain development.54

The presence of TRPC mRNA is also detected in the mouse dorsal root ganglion and nodose ganglion by in situ hybridization. TRPC1, TRPC3, and TRPC6 are found as the primary subsets from E12 on and then increase gradually to adult levels. TRPC2 has a reverse trend in development, while TRPC4, TRPC5, and TRPC7 expression starts from E12 and reaches a peak level at E18. Specifically, TRPC3 is detected exclusively in isolectin B4-positive cells, which are TRPV1-negative, while TRPC1 and TRPC2 localize in the neurofilament 200-positive large-size subclass of neurons.55

The omnipresent distribution of TRPCs in the nervous system suggests their importance to the development and function of the system. Because these proteins can form heterotetramers with each other, the heterogeneity of their spatiotemporal expression may be far more complex than what has been found so far.


During development, many neurons are generated, while about 70% of them are lost later in life because of natural cell death. This phenomenon was first studied in the twentieth century and has been found to occur during development of both the CNS and peripheral nervous system (PNS) in various species.56 The programmed neuronal cell death and survival of limited neuronal populations are believed to be essential for formation of appropriate neural networks and to delete incorrect connections.57 Neurotrophic factors (NTF) play important roles in neuronal survival. In fact, studies of neuronal survival led directly to the discovery and exploration of NTFs.56,58 Moreover, studies of CNS development have established that neuronal activity is also crucial for neurons to survive.59,60 In both NTF-induced and activitydependent survival, Ca2+ acts as a pivotal ion.

In the CNS, neuronal survival in the visual, olfactory, and auditory sensory systems was found to be afferent dependent.60 It is believed that activity of the target neurons is important for their survival. Depolarization promotes various neurons in the CNS to survive in a cultured system. When cultured in a nerve growth factor (NGF)- deprived medium, rat sympathetic neurons die within 3 days, while depolarization by elevating extracellular K+ prevents the death and supports neuronal survival.61 Activation of L-type voltage-gated Ca2+ channels (VGCC) and sustained elevation of Ca2+ in cytosol are required in depolarization-induced neuronal survival.62,63 L-type VGCC inhibitors suppress depolarization and neuronal survival,62,63 while the agonists of L-type VGCCs, as well as thapsigargin, which releases Ca2+ from the internal stores, can mimic the survival-promoting effect of depolarization by elevating cytosolic Ca2+ levels.61,64

Classic NTF-dependent neuronal survival has been thought to share a similar mechanism as activity-dependent survival. Stimulating neurons with NGF did not induce apparent cytosolic Ca2+ elevation,65,66 indicating that sustained Ca2+ elevation might not be needed for NTF-induced survival promotion. However, if intracellular Ca2+ concentration is kept at extremely low levels, NTFs cannot promote neuronal survival.61 Therefore, proper Ca2+ levels in the cytosol are needed for NTF function. Moreover, the protection by IGF-1 of granule cells exposed to low K+ medium depends on the activity of L-type VGCCs.67 Subsequent studies revealed that BDNF stimulation induces intracellular Ca2+ elevation in neurons and that this elevation is important for neuronal survival.54 BDNF binding to TrkB induces dimerization of TrkB, which in turn activates PLCγ, thereby stimulating TRPC channels to elevate the cytosolic Ca2+ level.

It is known that moderate intracellular Ca2+ elevation can promote neuronal survival through various pathways, including the PI3K-AKT pathway. Several NTFs (NGF, BDNF, GDNF, and IGF) can activate the PI3K-AKT cascade6870 to promote neuronal survival. In cerebellar granule neurons, phosphorylated AKT can inactivate FKHRL1. Inactivation of this Forkhead transcriptional regulator suppresses the expression of apoptotic genes.71 Active AKT can also phosphorylate BAD72 and caspase-973 directly to induce apoptotic machinery dysfunction. The AKT pathway can upregulate the activity of CREB and NF-κB, which are transcriptional factors known to promote neuronal survival.74,75 Ca2+ elevation can lead to phosphorylation of AKT independent of PI3K or MAP kinases.76 Moreover, Ca2+ elevation can be regulated by activation of AKT. Phosphorylation of L-type VGCCs by AKT is essential for IGF-1-induced L-type VGCC potentiation.67 The Ca2+/CaM-dependent protein kinase II can promote activity-dependent neuronal survival by inhibiting histone deacetylase-5 (HDAC5C), which is the repressor of MEF2, a transcriptional factor involved in neuronal survival.77,78

The production of NTFs can also be affected by intracellular Ca2+ elevation. In hippocampal neurons, neuronal activity can induce postsynaptic secretion of BDNF and NT3. The secretion is dependent on Ca2+ influx and release.79,80 Non-neuronal cells can also secrete NTFs in response to intracellular Ca2+ elevation. For example, astrocytes can release BDNF when stimulated with glutamate.81 Brain endothelial cells release BDNF in response to hypoxia.82 Vascular smooth muscle cells secrete NGF when stimulated with thrombin.83 These processes are Ca2+ dependent.8183 Together, these results suggest that during development or under pathological conditions, NTFs can be secreted in Ca2+-dependent manners to promote neuronal survival in non-cell autonomous ways.

It has also been known that improper Ca2+ elevation induces neuronal cell death. Under pathological conditions such as hypoxia,84 ischemia,85 trauma,86 and neurodegenerative disease,87 Ca2+ elevation is a key factor for neuronal death. Increases in the Ca2+ level can initialize apoptosis in many systems.88,89 Although it is not clear why changes in Ca2+ level lead to different outcomes, the Ca2+ set point hypothesis suggests that the Ca2+ concentration is the key.61 Another possibility is that Ca2+ influx from different routes can induce different fates of neurons, which is consistent with the fact that neurons have many routes for Ca2+ influx.90,91 Activation of NMDA receptors readily evokes neurotoxicity, although the activation induces an increase in the Ca2+ level equal to that induced by depolarization via elevating extracellular K+.91 The spatial and temporal patterns of the Ca2+ signal due to Ca2+ entry from different routes vary, and this may lead to activation of different downstream pathways91,92 that affect neuronal fate.


Members of the TRPC subfamily have roles in multiple processes, including neuronal development, survival, and proliferation of neural stem cells. TRPC1 is involved in mGluR1-mediated slow excitatory postsynaptic conductance (EPSC) in cerebellar Purkinje cells,93 in hippocampal glutamate-induced cell death,94 and in embryonic neural stem cell proliferation.53 TRPC2 may play a role in pheromone transduction in the vomeronasal system.95 TRPC3 is involved in BDNF-induced dendritic spine formation,96 cerebellar granule neuron (CGN) survival,54 and motor coordination.97 TRPC4 may have a role in neurite extension in post-mitotic neurons.98 TRPC5 is involved in controlling neurite extension and growth cone morphology15 in hippocampal neurons99 and fear-related behavior.100 TRPC6 plays essential roles in BDNF-mediated survival of CGNs during development54 and in dendritic growth,101 as well as synapse formation by hippocampal neurons.102 Recent studies also indicate that TRPC channels mediate muscarinic receptor-induced slow afterdepolarization in pyramidal cells of the cerebral cortex103 and neuroprotection promoted by plateletderived growth factor.104 TRPC channels also play a role in chemokine (C-C motif) ligand 2 (CCL2)-mediated neuroprotection in rat primary midbrain neurons.105 Among a variety of physiological functions of TRPC channels, promoting neuron survival makes them a promising target for future therapeutic strategies in diseases.

10.5.1. Signaling Pathways and Neuronal Survival

It has been known that neuronal survival can be regulated by intrinsic death pathways and extrinsic trophic signaling processes, among which neurotropin signaling is critical for neuron survival both in development and in adulthood.70,106109 The NTFs are a pleiotropic group of secreted growth factors that regulate multiple aspects of neuronal development, including neuronal survival. In the mammalian CNS, there are four NTFs, which are composed of a family of structurally related proteins: NGF, BDNF, neurotrophin 3 (NT-3), and NT-4. Neurotrophin binding to its receptor, usually together with intrinsic tyrosine kinase activity, triggers one or more intracellular signaling pathways responsible for neuronal survival.110,111 These pathways inhibit intrinsic apoptosis machinery from carrying out a cellular suicide program.112114 Two intracellular signaling pathways that are activated by RTKs and are crucial in promoting neuronal survival include the extracellular signal-regulated kinase (ERK)/cAMP response element-binding protein (CREB) pathway and the PI3K/AKT pathway.115117 These two pathways can activate both intracellular mechanisms and nuclear transcriptional mechanisms that inhibit cell death.

During CNS development, restriction of neuronal death by survival signaling is important for proper formation of neuronal networks,118 while in adulthood, neuronal death is mainly related to pathological conditions, including stroke, neurodegenerative diseases, and trauma.119,120 To protect against neuronal death, survival signaling is enhanced and neuroprotective mechanisms are activated to preserve neuronal survival. Loss or reduction in these intrinsic europrotections might contribute to or accelerate neuronal damage, whereas their activation might rescue neurons from brain injuries.

10.5.2. TRPCs as a Transducer of BDNF-Mediated Survival

TRPC3 and TRPC6 play key roles in neuronal survival via transmitting BDNF mediated signals (Figure 10.2). It has been found that RTKs can stimulate PLCγ to activate TRPC channels.28,121 BDNF is essential for survival of a variety of neurons,122 including CGNs74,123,124 and striatal neurons. In pontine neurons, BDNF triggers a nonselective inward current that resembles that of TRPC channels.34 In both CGNs and Xenopus laevis spinal neurons, TRPC channels are essential for BDNF-triggered growth cone turning.125127 On the basis of these findings, Jia et al. proposed that TRPC channels may transmit BDNF survival signals and promote CGN survival.54 They have examined the role of TRPCs in neuronal survival in both CGN cultures and that neonatal cerebellum. They found that TRPC3 and TRPC6 are required for BDNF-mediated neuronal protection, BDNF-triggered intracellular Ca2+ elevation, and BDNF-induced CREB activation. Overexpressing TRPC3 or TRPC6 markedly enhanced CREB phosphorylation and increased CREB-dependent transcription. Furthermore, overexpressing these channels protected CGNs against serum deprivation-induced cell death via CREB activation. In contrast, knocking down the expression level of TRPC3 or TRPC6 led to increased cell apoptosis in the neonatal cerebellum. Taken together, these findings provide in vitro and in vivo evidence that TRPC channels play a critical role in promoting neuronal survival and indicate that activation of CREB is a key downstream event for the neuronal protective effect of TRPC channels.

FIGURE 10.2. Possible mechanisms for TRPC channels in neuronal survival.


Possible mechanisms for TRPC channels in neuronal survival. NTFs and CCL2 activate PLC to cleave PIP2 into DAG and IP3. DAG and IP3 activate TRPC channels, and Ca2+ influx via TRPC channels promotes neuronal survival by the Ras/ERK- and CaM/ CaMK-CREB (more...)

A recent study using mice with a mutation in the TRPC3 gene revealed the importance of TRPC3 channels for Purkinje cell survival during development. The mutation causes an alteration in TRPC3 phosphorylation and abnormal gating of the channel, leading to cell death and ataxia in mice.128 These results suggest that the normal gating of TRPC3 channels is critical to initiate the downstream events for neuronal survival, while the aberrant opening of the channel could lead to neuronal death.

10.5.3. TRPCs in Neuroprotection against Neuronal Injury

TRPC1 has been reported to protect human SH-SY5Y neuroblastoma cells against salsolinol-mediated cytotoxicity129 and 1-methyl-4-phenylpyridinium ion (MPP+) -mediated neurotoxicity130 likely by inhibiting apoptosis. Both TRPC1 activation and TRPC1 over-expression protect SH-SY5Y cells from apoptosis. Similarly, the increase in TRPC1 protein expression decreased the level of proteins required for carrying out apoptosis, such as cytochrome C, Bax, and Apaf1, by unknown mechanisms. It is thus suggested that TRPC1 may inhibit apoptotic signaling to provide neuroprotection against agents that induce Parkinson's disease.

It has been recently reported that inhibition of TRPC channels suppresses the CCL2-mediated neuroprotection against HIV-1 transactivator protein (Tat) toxicity in rat neurons.105 TRPC channels are involved in the process of CCL2 protection by elevating intracellular Ca2+ and activating the ERK/CREB pathway in a manner similar to CGN survival promoted by TRPC3/TRPC6105 (Figure 10.2). Further research on functions of TRPC channels under pathologic conditions may provide new avenues for treatment of brain damage and neurodegenerative diseases.


Several approaches have been employed to study TRPCs in mammalian cells, including expression of the wild-type or dominant-negative form of TRPCs in exogenous expression systems, use of specific antibodies, and pharmacological inhibitors or agonists. Moreover, generation of transgenic mice and genetic ablation in knockout mice are also powerful approaches to investigate TRPCs in vivo. Perhaps one of the most convenient ways to specifically manipulate TRPCs at the present time is to use wild-type and dominant-negative constructs of TRPCs. As the investigation of TRPCs evolves, several pharmacological inhibitors against certain subtypes of TRPCs have been developed, such as Pyr3 for TRPC3. It is important to realize the limitations of these approaches. For instance, TRPC channels formed by overexpressed TRPC proteins in heterologous expression systems might be different from the endogenous channels because overexpression might lead to formation of homomeric channels. Moreover, the specificities of pharmacological inhibitors and antibodies commonly used are not entirely clear. For example, SKF96365, which is widely used to inhibit TRPCs,126,131 can inhibit both receptor-mediated and voltage-gated Ca2+ entry.131 La3+, which is used to inhibit several TRPCs,15,132134 can inhibit nonspecific Ca2+ channels and mitochondrial cationic channel(s).135 At present, one of the biggest hurdles to the study of possible roles of TRPCs in vivo is the lack of specific antagonists for TRPCs. In addition to genetic interference and pharmacological inhibition, generation of specific antibodies against the pore region of TRPCs to block the ion flow could greatly help the study of TRPC functions (see Chapters 6 and 7). Moreover, TRPC proteins can form homo- and heteromeric channels. Therefore, to investigate the contribution of an individual channel protein to channel functions is a challenge. Additionally, the interpretation of the data obtained through experimental modulations of TRPC channels may be hampered by the fact that the inhibition or activation may affect other channels, receptors, or intracellular molecules. Studying the regulation of TRPC channels in both heterologous expression systems and native physiological systems would be important for a better understanding of these channels. For the latter, the generation of conditional TRPC knock-out mice and/or the use of RNAi gene silencing could be powerful tools (see Chapter 8).


TRPC channels are activated by GPCRs and RTKs through a PLC-dependent mechanism. Because both GPCRs and RTKs are important for neuronal survival, TRPC channels could serve as a sensor of the extracellular signals that activate these receptors in the CNS. Accumulating evidence so far supports a critical role of TRPCs in neuronal survival under physiological conditions. These findings have laid a foundation for further investigating their possible roles in pathological conditions. The broad expression profiles of TRPCs in the CNS point to the possibility that they might also participate in the pathogenesis of neurodegenerative disorders, such as Alzheimer’s disease and Parkinson’s disease. Future studies will show whether and how these channels contribute to neuronal survival in pathological conditions.

It should be pointed out that TRPM7 channels are involved in ischemic neuronal death.136 Suppression of TRPM7 protein expression in hippocampal neurons prevents delayed neuronal death in global cerebral ischemia.137 This raises a question as to why different members of the TRP family, almost all of which mediate Ca2+ influx, have different roles in neuronal fate. Hopefully, mediators underlying the pro-survival role of TRPC channels and the pro-death role of TRPM7 in neurons will be uncovered in the near future. Factors that determine whether TRP channels promote or inhibit neuronal survival also warrant future exploration. Identification of these factors may be critical for the development of strategies to target the TRP cascade in combating neurological diseases.


This work was supported by a grant from the 973 Program (2011CB809000) of China.


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