Abstract
The TRP-canonical (TRPC) subfamily, which consists of seven members (TRPC1–TRPC7), are Ca2+-permeable cation channels that are activated in response to receptor-mediated PIP2 hydrolysis via store-dependent and store-independent mechanisms. These channels are involved in a variety of physiological functions in different cell types and tissues. Of these, TRPC6 has been linked to a channelopathy resulting in human disease. Two key players of the store-dependent regulatory pathway, STIM1 and Orai1, interact with some TRPC channels to gate and regulate channel activity. The Ca2+ influx mediated by TRPC channels generates distinct intracellular Ca2+ signals that regulate downstream signaling events and consequent cell functions. This requires localization of TRPC channels in specific plasma membrane microdomains and precise regulation of channel function which is coordinated by various scaffolding, trafficking, and regulatory proteins.
Access provided by Autonomous University of Puebla. Download chapter PDF
Similar content being viewed by others
Keywords
1 Introduction
TRPC channels were first identified as molecular components of the store-operated calcium entry (SOCE) channels (Ambudkar et al. 2007; Parekh and Putney 2005; Venkatachalam and Montell 2007). SOCE is an ubiquitous Ca2+ entry mechanism that is activated in response to stimulation of plasma membrane receptors coupled to phosphatidylinositol 4,5-bisphosphate (PIP2) hydrolysis, inositol 1,4,5-triphosphate (IP3) generation, and IP3 receptor (IP3R)-mediated Ca2+ release from the endoplasmic reticulum (ER). The primary trigger for activation of SOCE is depletion of the ER-Ca2+ store, while refilling of this store leads to inactivation. The first store-operated Ca2+ current to be identified (ICRAC) was the inwardly rectifying and highly Ca2+-selective current that was measured in mast cells and T lymphocytes (Hoth et al. 1993; Hoth and Penner 1992; Parekh and Penner 1997). The channel mediating this current was termed calcium release-activated calcium (CRAC) channel. Later studies revealed currents with varying electrophysiological characteristics in other cell types (Liu et al. 2004; Parekh and Putney 2005). TRPC channels were proposed as possible molecular components of such channels and indeed, several TRPC members have been reported to contribute to SOCE, although data for some TRPCs are not very consistent. TRPC1 was the first mammalian TRPC channel to be cloned (Wes et al. 1995; Zhu et al. 1995), and early studies established that when activated by conditions resulting in store depletion, it is required for the generation of a relatively Ca2+-selective cation current that was termed ISOC (store-operated Ca2+ current; Liu et al. 2003) to distinguish it from ICRAC. TRPC1 has been most consistently demonstrated to contribute to SOCE in a variety of cell types (Ambudkar et al. 2007; Beech 2005), although heterologous expression of the channel does not always result in consistent functions.
The critical mechanism that senses the status of ER-[Ca2+] and regulates activation of plasma membrane channels mediating SOCE remained a challenge for more than two decades. This component has now been elucidated, with the discovery of STIM1 as the ER Ca2+-sensor protein involved in regulating the plasma membrane channels. Further, Orai1 has been established as the pore-mediating component of CRAC channels. Of further interest is the finding that activation of TRPC channels following store depletion is dependent not only on STIM1 but also on Orai1 (discussed in detail below). The exact mechanism(s) that regulate TRPC channels in the non-store-operated mode is not yet clearly elucidated, although diacylglycerol (DAG), a product of PIP2 hydrolysis, has been suggested as an endogenous ligand.
2 Physiological Functions of TRPC Channels
The physiological functions ascribed to TRPCs have been determined in cell cultures and animal models. Some human diseases are also associated with loss or gain of channel function. In cell lines and primary cell cultures, endogenous TRPC channel function has been assessed by decreasing protein expression using shRNA or siRNA (Table 1). TRPC1-mediated Ca2+ entry regulates endogenous glioma Cl− channels to facilitate cell migration by promoting cell shape and volume changes (Cuddapah et al. 2013). The channel is also vital for maintaining permeability of endothelial cell barrier, promoting wound healing following injury to the intestinal epithelial layer and protection against cell cytotoxicity (Bollimuntha et al. 2005b; Paria et al. 2004). Other physiological functions that have been attributed to TRPC1 include cell proliferation and synaptic plasticity (Fiorio Pla et al. 2005; Li et al. 2012a; McGurk et al. 2011). Knocking down endogenous TRPC2 levels or expression of a dominant-negative isoform of TRPC2 in rat thyroid FRTL-5 cells severely impacted cell proliferation and migration, as well as cellular adhesion (Sukumaran et al. 2013). TRPC2 and anoctamin 1 have been proposed to function synergistically to modulate iodide transport in thyroid cells (Viitanen et al. 2013). TRPC3 is involved in proliferation and differentiation of various cell types, such as myoblasts, cardiac fibroblasts, and primary T cells (Harada et al. 2012; Wenning et al. 2011; Woo et al. 2010). In some cells, more than one TRPC channels have been shown to regulate the same physiological event. For example, TRPC3, TRPC4, and TRPC5 facilitate in vitro endothelial tube formation by promoting proliferation of endothelial cells (Antigny et al. 2012). TRPC5 and TRPC6 regulate migration of fibroblasts and kidney podocytes in an antagonistic manner, whereby TRPC5 activates Rac1 to promote motility but TRPC6 activates RhoA to inhibit motility (Tian et al. 2010). TRPC5 also plays an important role in facilitating migration of vascular smooth muscle cells, as well as regulating neurite extension and growth cone morphology of hippocampal neurons (Greka et al. 2003; Tian et al. 2010; Xu et al. 2006). TRPC6 regulates the growth of pontine neurons (in addition to TRPC3) (Li et al. 2005) and prostate cancer epithelial cells (Thebault et al. 2006).
The physiological functions of TRPC channels has been revealed by studies using knockout mouse models (discussed in further detail in Chapters 2 to 8 of volume 1, “TRPC1”, “TRPC2”, “TRPC3: A Multifunctional Signaling Molecule”, “TRPC4- and TRPC4-Containing Channels”; “TRPC5”, “TRPC6: Physiological Function and Pathophysiological Relevance” and “Transient Receptor Potential Canonical 7: A Diacylglycerol-Activated Non-selective Cation Channel”). In addition to knockout mouse models, mice expressing dominant-negative isoforms of TRPC3, TRPC4, and TRPC6 reveal that these channels are involved in the development of cardiac hypertrophy via a calcineurin-NFAT signaling pathway (Wu et al. 2010). Various dominant-negative isoforms of TRPCs have been generated, e.g., pore-dead channel created by mutations in the pore region. Others, such as the TRPC3 N-terminus (amino acids 1–302), also exert dominant-negative effects when overexpressed by disrupting channel assembly since TRPCs interact via their N-terminal regions (Balzer et al. 1999). In the case of TRPC4, an N-terminal fragment that includes the first ankyrin-like repeat has been used (Schindl et al. 2008). In other studies, TRPC function has been revealed by using disease models. A mouse model for Parkinson’s disease (PD) shows the vital role of TRPC1 in maintaining calcium homeostasis, promoting neuronal survival to limit neuronal degeneration, and possibly slowing down or preventing the onset of progression of PD. PD-associated symptoms are ameliorated by heterologous expression of TRPC1 in neuronal cells or in vivo intranigral injection of TRPC1-containing adenovirus particles in PD mouse model (Selvaraj et al. 2009, 2012).
A number of other mouse models also reveal important information regarding TRPC channel regulation. Physiological functions attributed to TRPC1 are severely affected in caveolin-deficient (Cav-1−/−) and Homer1-deficient (Homer1−/−) mice. Knocking out caveolin-1 (Cav-1) results in mislocalization of TRPC1 due to aberrant trafficking, leading to impaired channel function that significantly reduces salivary gland fluid secretion (Pani et al. 2012). Loss of Homer1, a scaffolding protein that mediates TRPC1 interaction with the IP3R, causes aberrant calcium signaling resulting in skeletal myopathy (Stiber et al. 2008). The Mecp2 mutant mice are a model system for Rett syndrome, which is caused by loss-of-function mutations in the Mecp2 gene. These mice display sensory and motor abnormalities due to loss of TRPC3 function in hippocampal neurons, although potential contributions from TRPC6 or TRPC7 have not been ruled out (Li et al. 2012b). Interestingly, in some studies, an increase of TRPC expression and function has been proposed to underlie disease onset and/or progression. Studies with Duchenne muscular dystrophy (mdx) mice demonstrate an increase in TRPC1-mediated Ca2+ influx induces muscle damage (Gervasio et al. 2008; Williams and Allen 2007). Expression of TRPC1, TRPC5, and TRPC6 is significantly elevated in adrenal medulla of Ossabaw miniature pigs are used to study the metabolic syndrome or pre-diabetes state (Hu et al. 2009). Perturbations in Ca2+ signaling and homeostasis have been correlated with increased TRPC3 expression and function in cardiomyocytes obtained from muscle LIM protein knockout mice (model for the myocardial disorder, dilated cardiomyopathy) (Kitajima et al. 2011) and spontaneously hypertensive rats (model for hypertension) (Adebiyi et al. 2012; Bush et al. 2006; Noorani et al. 2011). TRPC7 has been implicated in myocardial apoptosis failure as its expression is upregulated in Dahl salt-sensitive rats with heart failure and has been proposed to be a novel target for treatment of heart failure (Satoh et al. 2007).
The genes encoding TRPC channels have also been linked to various human diseases, such as cardiovascular, pulmonary, and neurological, as well as cancer (Nilius and Owsianik 2010). For example, trpc5 and trpc6 loci are linked with infantile hypertrophic pyloric stenosis, a very common condition of stomach obstruction that is characterized by projectile vomiting. Increased trpc6 promoter activity and TRPC6 expression have been linked to the development of idiopathic pulmonary arterial hypertension, which is caused by excessive proliferation of pulmonary artery smooth muscle cells. Nonetheless, the only TRPC-related channelopathy reported so far is focal and segmental glomerulosclerosis (FSGS), which is linked to a mutation of the trpc6 gene. These mutations resulted in alterations of residues in the N- and C-termini, leading to significantly elevated TRPC6-mediated calcium signaling that may affect channel interaction with podocyte structural proteins, leading to defects in the filtration barrier. Alternatively, the elevated calcium signaling mediated via TRPC6 may lead to apoptosis, resulting in a defective permeability barrier (Mukerji et al. 2007; Nilius and Owsianik 2010). Nonetheless, some TRPC6 variants linked to FSGS have also been reported to not cause any change in channel activity (Reiser et al. 2005).
3 TRPC Channel Complexes
Much of the initial insights into TRPC protein interactions are based on studies with the Drosophila TRP channel which is localized in the Drosophila eye and plays a critical role in phototransduction (Venkatachalam and Montell 2007). This TRP channel resides in a multiprotein signalplex with proteins that are important for proper channel assembly, retention, activity, regulation of phototransduction, and downstream signaling. The scaffolding protein INAD forms the core of this complex since it has the ability, via multiple PDZ domains, to bind to numerous signaling proteins and serve as a platform for their interaction with TRP and regulation of channel function (Venkatachalam and Montell 2007). Critical amino acid sequences that are conserved in TRP channel families appear to be involved in these various, but specific, protein–protein interactions. These include the coiled-coiled domain, ankyrin repeat region, calmodulin- and lipid-binding domains, as well as other less well-characterized protein binding domains. Since mammalian TRPC proteins share many of the same structural components as the Drosophila TRP channel, it has been hypothesized that the individual TRPC protein is also capable of forming homomeric or heteromeric interactions with other TRPC channels and signaling proteins. It is now well established that a number of key signaling and scaffolding proteins are associated with mammalian TRPC channels (Ambudkar et al. 2006; Ambudkar and Ong 2007; Kiselyov et al. 2007).
3.1 TRPC1
TRPC1 interacts with other TRPCs to form channels with diverse properties, ranging from relatively Ca2+-selective to non-selective (Ca2+ vs. Na+) (Cheng et al. 2013). In human submandibular gland (HSG) cells, TRPC1 contributes to a relatively Ca2+-selective cation channel, possibly via a homomeric TRPC channel (Liu et al. 2004). Several TRPCs are endogenously expressed in cells, for example, TRPC1 and TRPC3 in HEK293 cells and neuronal cells (Zhu et al. 1995, 1996). Based on the association of TRPC1 and TRPC3 in heterologous expression systems, it can be suggested that the endogenous channels can also assemble in heteromeric complexes. Indeed, endogenous heteromeric TRPC channels have been described in different cell types: e.g., TRPC1 + TRPC3 in HSY cells (Liu et al. 2005), TRPC1 + TRPC3 + TRPC7 in HEK293 cells (Zagranichnaya et al. 2005), TRPC1 + TRPC4 in mesangial cells (Sours-Brothers et al. 2009) and endothelial cells (Sundivakkam et al. 2012), and TRPC1 + TRPC5 in neuronal cells, vascular endothelial cells, and vascular smooth muscle cells (Goel et al. 2002; Shi et al. 2012; Strubing et al. 2001; Xu et al. 2006). TRPC1 forms a macromolecular complex with TRPC6, SERCA, and IP3R following passive depletion of the ER-Ca2+ stores in human platelets (Redondo et al. 2008).
TRPC1 also interacts with non-TRPC channels, such as Orai1 (Cheng et al. 2008; Lu et al. 2010), TRPV4 (Ma et al. 2010, 2011), and TRPV6 (Schindl et al. 2012). The association with Orai1 is a critical determinant of TRPC1 function (further discussed below). Although it is unclear whether there is a physical interaction between the two channels, studies have clearly established that Orai1 and TRPC1 form distinct STIM1-gated channels in the membrane that are activated following store depletion (Cheng et al. 2008; Lu et al. 2010). In a recent study, a splice variant of TRPC1 has been shown to regulate the activity of Orai1 (Ong et al. 2013). TRPC1 + TRPV4 forms a heteromeric channel involved in SOCE in vascular smooth muscle cells as well as endothelial cells (Ma et al. 2010, 2011). TRPC1 can also interact with and negatively regulate TRPV6 channel activity, without generation of a heteromeric channel, in HEK293 cells (Schindl et al. 2012).
In addition to calcium channels, TRPC1 interacts with a wide range of signaling proteins, as well as scaffolding and trafficking proteins (Table 2). The TRPC1 signaling complex contains key Ca2+ signaling proteins that function upstream in the agonist-activated signaling cascade, such as PLC, CaM, Gq/11, IP3R, PMCA, SERCA, and STIM1 (Cheng et al. 2008; Heo et al. 2012; Huang et al. 2006; Lockwich et al. 2000; Lu et al. 2010; Ng et al. 2009; Ong et al. 2007; Pani et al. 2009; Redondo et al. 2008; Selvaraj et al. 2012 ; Singh et al. 2002; Sundivakkam et al. 2009; Tang et al. 2001; Yuan et al. 2003). Such findings have led to the proposal that TRPC1 channel complexes are composed of proteins from both ER and plasma membranes and likely represent cellular microdomains where these two membranes are in close proximity to each other. The interaction with STIM1 is critically required for channel activation following store depletion. Additionally, TRPC1 activity is also regulated via its binding to IP3R as it has the CaM-/IP3R-binding (CIRB) domain in the C-terminus. Both CaM and IP3R bind competitively to TRPC1 to modulate channel activity, with IP3R involved in channel activation and CaM regulating the Ca2+-dependent feedback inhibition (Singh et al. 2002; Tang et al. 2001). It is interesting that the STIM1- and IP3R-binding domains lie in close proximity in the C-terminus of TRPC1. However, it is yet unclear whether STIM1 and the IP3R are simultaneously involved in activation of TRPC1. It is interesting to speculate that the level and type of physiological stimuli may have an impact on the channel regulation. Interaction between TRPC1 and IP3R has been reported to be mediated by RhoA in endothelial cells (Mehta et al. 2003) and Homer1 in HEK293 cells (Kiselyov et al. 2007). Additionally, RhoA (Mehta et al. 2003) and other proteins such as Cav-1 (Ambudkar et al. 2006; Brazer et al. 2003; Lockwich et al. 2000) and β-tubulin (Bollimuntha et al. 2005a) affect surface expression of TRPC1. TRPC1 interaction with Cav-1 and RhoA is suggested to mediate its localization in lipid raft domains where TRPC1 channels are assembled and activated in response to store depletion (Pani et al. 2008). Further studies will be required to establish the exact contributions of each interacting protein in the regulation of TRPC1.
3.2 TRPC2
While the human Trpc2 is a pseudogene and does not form a functional channel (Wes et al. 1995; Zhu et al. 1995), TRPC2 in other mammals (e.g., rat, bovine, and mouse) forms functional channels in different cell types and tissues, such as the vomeronasal organ (VNO), testis, spleen, and liver (Liman et al. 1999 ; Vannier et al. 1999; Wissenbach et al. 1998). Few studies have looked at the interactions between TRPC2 and other TRPC channels and various signaling proteins. When heterologously expressed in HEK293 cells, TRPC2 interacts with endogenous Homer1 and IP3R (Yuan et al. 2003), but not with other TRPCs (Hofmann et al. 2002). Nonetheless, TRPC2 has been shown to interact with TRPC6 and signaling proteins, erythropoietin receptor, IP3R, and PLCγ in primary erythroblasts (Chu et al. 2004; Tong et al. 2004). Additionally, TRPC2 forms a signaling complex with the receptor-transporting protein 1 (RTP1), Homer1, and IP3R in the VNO (Mast et al. 2010). Other signaling proteins that interact with TRPC2 include STIM1 (Huang et al. 2006) and CaM (Tang et al. 2001; Yildirim et al. 2003). TRPC2 has been reported to co-localize with anoctamin 1 in the vomeronasal epithelium (Dibattista et al. 2012), although the interaction between the two proteins has not been confirmed using other techniques such as immunoprecipitation, FRET and TIRF.
3.3 TRPC3
While TRPC3, TRPC6, and TRPC7 share considerable homology in their amino acid sequences, as well as modes of activation, their physiological properties and function are quite distinct (Owsianik et al. 2006; Putney 2005). Depending on the level of expression and its heteromeric interactions with other TRPC channels, TRPC3 can form both store-independent and store-dependent channels in different cell types. As shown in Table 2, TRPC3 interacts with almost every member of the TRPC subfamily, as well as TRPM4 (Park et al. 2008) and Orai1 (Liao et al. 2007; Woodard et al. 2010). A fairly comprehensive list of TRPC3-associated proteins was identified in an earlier proteomic study, including proteins associated with Ca2+ entry and signaling, neural growth, vesicle fusion, mitochondria, endocytosis, actin cytoskeleton, and microtubules (Lockwich et al. 2008). As noted above, TRPC1 + TRPC3 and TRPC1 + TRPC3 + TRPC7 contribute to SOCE. TRPC3 has been suggested to act concertedly with TRPC1 to mediate SOCE in H19-7 hippocampal neuronal cells (Wu et al. 2004). Store dependence of TRPC3 might also be mediated by its interactions with Orai1 (Liao et al. 2007) and STIM1, the latter likely dependent on an interaction of TRPC3 with TRPC1 (Yuan et al. 2007). In addition to activation via the G protein/PLC-mediated pathway, heteromeric TRPC3 + TRPC4 channels in porcine aortic endothelial cells are redox activated (Poteser et al. 2006). Further research is required to delineate the molecular interactions involved in regulating TRPC3 channel assembly and function.
As seen with TRPC1, TRPC3 also interacts with a number of key Ca2+ signaling proteins involved in receptor-stimulated Ca2+ mobilization, such as PIP2 hydrolysis (PLCβ, Gq/11), IP3R, and the calcium-sensing receptor (CSR) (Table 2). SERCA and PMCA pumps also co-immunoprecipitate with TRPC3 (Bandyopadhyay et al. 2005; Kiselyov et al. 2007; Lockwich et al. 2001, 2008). Further, scaffolding proteins such as Homer or RACK1 interact with TRPC3 and modulate its interaction with IP3R (Bandyopadhyay et al. 2008; Kiselyov et al. 2007). A number of protein interactions are involved in plasma membrane localization of TRPC3 (further discussed below).
3.4 TRPC4
TRPC4 is most closely related to TRPC5, sharing 65 % amino acid identity, but both proteins diverge in the last 220 amino acids. There is general consensus that TRPC4 forms an SOC channel even though it has been shown to form constitutively active or store-independent channels in some studies (Parekh and Putney 2005; Venkatachalam and Montell 2007). Heteromeric interactions have been described between TRPC4 and other TRPCs (Table 2) (Alvarez et al. 2008; Ambudkar et al. 2006; Ambudkar and Ong 2007; Antoniotti et al. 2006; Chen et al. 2009; Cheung et al. 2011; Murata et al. 2007; Phelan et al. 2013; Poteser et al. 2006; Puram et al. 2011; Riccio et al. 2009; Sabourin et al. 2009; Sundivakkam et al. 2012; Woo et al. 2008; Zimmermann et al. 2011). As described above for TRPC1 and TRPC3, TRPC4 heteromultimerizes with TRPC6 and, via its direct interaction with STIM1, forms a TRPC4 + TRPC6 channel that is store-dependent (Yuan et al. 2007). In intestinal smooth muscle cells, TRPC4 and TRPC6 channels are simultaneously activated by muscarinic receptors and contribute independently to the muscarinic receptor-induced cation current. Therefore, TRPC4 and TRPC6 channels couple muscarinic receptors to depolarization of intestinal smooth muscle cells and voltage-activated Ca2+ influx and contraction, thereby accelerating small intestinal motility in vivo (Ambudkar 2009; Tsvilovskyy et al. 2009). The interaction between STIM1 and TRPC4 was proposed to be the activation mechanism of the heteromeric TRPC1 + TRPC4 channels in glomerular mesangial cells (Sours-Brothers et al. 2009). Another protein vital for TRPC4 activity is protein 4.1, which functionally links TRPC4 to the actin cytoskeleton and spectrin in endothelial cells (Cioffi et al. 2005). Protein 4.1 and another adaptor protein, SESTD1, have been proposed to stabilize TRPC4 in a macromolecular complex associated with the cytoskeleton. SESTD1 associates with both TRPC4 and TRPC5 via the CIRB domain and functions to couple TRPC channel activity to lipid signaling (Miehe et al. 2010).
Signaling proteins involved in interactions with TRPC4 include the PDZ-domain proteins NHERF and ZO1 via the “VTTRL” sequence in the C-terminus of TRPC4 and PLC (Tang et al. 2000), as well as fyn (Odell et al. 2005). The dynamic interplay between tyrosine kinases, TRPC4 and NHERF, regulates cell surface expression and activation of the channel. TRPC4 also associates with the caveolae where growth factor receptor signaling proteins as well as NHERF-binding proteins, such as ezrin, are localized (Torihashi et al. 2002). It has been suggested that the interaction with NHERF and Z01 provide a scaffold to position the channel in the apical or lateral regions of polarized cells such as endothelial cells.
3.5 TRPC5
Heterologously expressed TRPC5 forms a non-selective channel that can be activated by receptor stimulation but not store depletion in HEK293 (Schaefer et al. 2000), PC12 (Ohta et al. 2004), and murine stomach cells (Lee et al. 2003) or directly by Ca2+ in HEK293 cells (Blair et al. 2009; Gross et al. 2009). TRPC5 can potentially form multimeric channels with other TRPCs (Table 2), e.g., TRPC1 + TRPC5 in neurons, vascular endothelial cells, and vascular smooth muscle cells (Goel et al. 2002; Shi et al. 2012; Strubing et al. 2001). Heterologously expressed TRPC5 forms a heteromeric channel with TRPC4 (Schindl et al. 2008). TRPC5 also has the sequence “VTTRL” in its C-terminus that mediates its interaction with the PDZ-binding proteins, NHERF and ezrin/moesin/radixin-binding phosphoprotein 50 (EBP50) (Obukhov and Nowycky 2004; Tang et al. 2000). NHERF mediates TRPC5 association with PLCβ and also regulates surface expression of TRPC5, whereas EBP50 links the channel to the actin cytoskeleton and modulates its activation kinetics following cell stimulation. Two CaM-binding sites located in the C-terminus of TRPC5 are involved in modulating channel activity (Tang et al. 2001). While myosin light chain kinase (MLCK) and PKC have been shown to regulate TRPC5 function, it is not clear whether these kinases exert their effects directly on the channel or indirectly by modulating the status of the actin cytoskeleton. Inhibition of MLCK activity adversely impacts channel activation, whereas PKC regulates channel desensitization following agonist stimulation. Additionally, activation of MLCK by Ca2+/CaM has been proposed to prolong channel activity by enhancing surface expression of TRPC5 (Kim et al. 2006b; Shimizu et al. 2006). Trafficking of TRPC5 to specific sites in the hippocampal neurons is determined by its interaction with the exocyst component protein stathmin-2, SNARE proteins, and other trafficking proteins such as dynamin, clathrin, and MxA (Goel et al. 2005; Greka et al. 2003). Moreover, the neuronal calcium sensor-1 (NCS-1) binds to the C-terminus of TRPC5 (Hui et al. 2006) and is involved in retardation of neurite outgrowth by TRPC5 homomeric channel (Bezzerides et al. 2004).
3.6 TRPC6
TRPC6 has been widely shown to be activated by DAG and not by internal Ca2+ store depletion (Dietrich et al. 2005; Putney 2005). Nonetheless, several studies report that activation of TRPC6 by store depletion is mediated by its association with Orai1 (Liao et al. 2007) and TRPC4 (which directly binds STIM1) (Yuan et al. 2007). Heteromeric TRPC6 channels have also been reported in different cell types, such as TRPC3 + TRPC6 in pontine neurons (Li et al. 2005) and prostate cancer epithelial cells (Thebault et al. 2006) and TRPC6 + TRPC7 in A7r5 cells (Maruyama et al. 2006). TRPC6 channel activity is determined via its interactions with different signaling proteins. The tyrosine kinase, fyn, interacts with TRPC6 and modulates channel activity via tyrosine phosphorylation in COS-7 cells (Hisatsune et al. 2004). Stimulation of neuronal PC12D cells with acetylcholine results in formation of a multiprotein complex of TRPC6, M1 mAChR and PKC, and DAG production. While DAG activates TRPC6, DAG-activated PKC phosphorylates the channel to inhibit it (Kim and Saffen 2005).
TRPC6 also undergoes trafficking to the plasma membrane, and several proteins that associate with the channel have a role in this process, such as enkurin (Sutton et al. 2004), actinin, actin, and drebrin (Goel et al. 2005), and endocytic vesicle-associated proteins (Goel et al. 2005; Lussier et al. 2005). TRPC6 also contains the conserved CIRB domain in the C-terminus, and CaM reportedly regulates TRPC6 activation (Tang et al. 2001; Yuan et al. 2003).
3.7 TRPC7
Since the first isolation of TRPC7 by screening the fetal brain and caudate nucleus cDNA libraries (Nagamine et al. 1998), there are relatively few studies that report its properties and function. Both store-dependent and store-independent modes of activation, as well as constitutive activation, have been reported for TRPC7 (Numaga et al. 2007). Multimeric TRPC1 + TRPC3 + TRPC7 channels function as SOC channels, whereas TRPC3 + TRPC7 channels appear to be DAG-activated channels, in HEK293 cells (Zagranichnaya et al. 2005). Additionally, function of TRPC7 has been reported to be modulated by cGMP-dependent protein kinase 1α (Yuasa et al. 2011), CaM, IP3R, and PIP2 (Ju et al. 2010; Mery et al. 2001; Tang et al. 2001; Yuan et al. 2003). Little is known about the mechanisms regulating the trafficking and localization of TRPC7, even though it has been shown to interact with IP3R, CaM, and MxA (Table 2).
4 Regulation of TRPC Channel Function by Intracellular Ca2+ Store Depletion
As discussed above, all TRPC channels are activated in response to stimulation of plasma membrane receptors that result in PIP2 hydrolysis. Some TRPCs are regulated by store depletion induced following stimulation by physiological agonists as well as treatment of cells with passively depleting agents such as thapsigargin and cyclopiazonic acid. Furthermore, in these cases, channel function is blocked by conditions that inhibit SOCE, such as the application of 1 μM Gd3+ and 10 μM 2APB. Typically, TRPC1 and TRPC4 have been suggested to be store-operated while TRPCs 3, 5, 6, and 7 have shown to be store-independent. The mechanisms by which store-independent regulation of TRPC channels occurs, presumably via PIP2 hydrolysis or DAG, are not very well established. Here we will summarize the presently available data on the regulation of TRPC channels by store depletion.
4.1 Role of STIM1
Considerable progress has been made regarding the TRPC channels that contribute to SOCE. In 2005, STIM1 was identified as the ER calcium sensor that regulates SOCE. STIM1 is diffusely localized in the ER in resting conditions, and upon Ca2+ store depletion, it aggregates and translocates to the periphery of the cells where it interacts with both Orai1 and TRPC channels in specialized ER-plasma membrane (PM) junctional domains. In these regions, the ER and plasma membrane come in close proximity to each other (Cheng et al. 2013; Hogan et al. 2010; Liou et al. 2005; Roos et al. 2005). The Orai channel family is comprised of three isoforms (Orais 1, 2, and 3), all of which have four transmembrane domains. Orai1 has been suggested to function as a tetramer (Hogan et al. 2010; Ji et al. 2008; Penna et al. 2008) and more recently as a hexamer based on crystal structure (Hou et al. 2012). The discovery of STIM1 and Orai1 led to the identification of the long sought-after components of the CRAC channel. STIM1 and Orai1 together are sufficient to reconstitute CRAC channel activity, with the C-terminal SOAR domain (aa 344–442) in STIM1 being the region involved in gating Orai1 and generating ICRAC (Hogan et al. 2010; Yuan et al. 2009). Numerous reports have demonstrated that STIM1 also interacts with members of the TRPC channel family and that it is necessary for gating TRPC channels (Cheng et al. 2013; Lee et al. 2010). Furthermore, TRPC heteromers that contain either TRPC1 or TRPC4 can be activated by STIM1. Thus, TRPC3 or TRPC6, likely non-store-operated channels, can appear to be regulated by STIM1 if they are assembled in the channel with TRPC1 or TRPC4 (Huang et al. 2006). The critical role of STIM1 in TRPC regulation [discussed in reviews by Cheng et al. (2013), Worley et al. (2007), and Lee et al. (2010)] is shown by the following data: (1) STIM1 and TRPCs co-immunoprecipitate and this association increases following store depletion; (2) the binding of STIM1 and TRPC1 has been confirmed by GST-fusion protein pull-down assays; (3) TRPC-mediated Ca2+ entry in response to store depletion is completely abolished by the knockdown of endogenous STIM1; (4) co-expression of TRPC1 and STIM1 induces an increase in store depletion-induced Ca2+ influx as well as ISOC; (5) endogenous TRPC function is suppressed by heterologous expression of dominant-negative STIM1 constructs; and (6) the STIM1D76A mutant, which induces constitutive Orai1 activation, also mediates spontaneous TRPC channel function. In aggregate, all these data provide convincing support that STIM1 regulates TRPC channel activation and function. Structure-function analysis of STIM1 has revealed crucial information regarding STIM1 domains involved in the interaction with TRPCs. The ERM (ezrin/radixin/moesin) domain (aa 251–535) located within the STIM1 cytosolic carboxyl terminus has been shown to bind selectively to some TRPC channels, e.g., TRPC1, TRPC2 and TRPC4, but not TRPC3, TRPC6, and TRPC7. As mentioned above, channels that cannot bind to STIM1 can be regulated by it if they are assembled in a heteromeric channel complex with TRPCs that bind STIM1. Nonetheless, it is notable that several studies with heterologous expression of TRPCs and STIM1 have failed to demonstrate the involvement of these channels in SOCE. It might be important to consider the assembly of TRPC channel complexes in such studies as other components might be essential in the regulation of these channels.
Binding of the ERM domain of STIM1 to TRPC channels is not sufficient for channel activation. A lysine-rich domain (referred to as polybasic tail or K domain) located at the C-terminal end of STIM1 has been established as the region that is involved in gating TRPC channels. Deletion of the STIM1-K domain affected TRPC channel activity but not binding to STIM1. The mechanism underlying the gating of TRPC channels by STIM1 has been revealed in a study demonstrating that the positively charged lysine residues (684KK685) in STIM1 interact electrostatically with negatively charged conserved aspartate residues in TRPC1 (639DD640), which leads to gating of the channel (Zeng et al. 2008). When the negative charges in TRPC1 are neutralized by substituting lysine (K) with alanine (A), channel activation by STIM1 is blocked. Moreover, swapping the charges between TRPC1 and STIM1 induces recovery of channel gating and function, providing conclusive evidence for the gating of TRPC1 by STIM1. Remarkably, the negatively charged sequence in TRPC1 C-terminus is highly conserved among TRPC family members, including TRPC3, TRPC4, TRPC5, and TRPC6 (Zeng et al. 2008). Thus, it was proposed that other TRPCs also have the inherent capacity to be gated by STIM1, although not all TRPCs bind directly to STIM1. Further studies need to be carried out to conclusively establish which TRPCs can bind to and are gated by STIM1, especially with regards to endogenous TRPC channels. Such information is crucial for understanding how store-dependent TRPC channels are assembled and regulated.
4.2 Role of Orai1
A very significant finding reported by several groups of researchers is that TRPC channel activation is not only dependent on STIM1 but also requires Orai1. Conclusive findings show that stimulation of cells results in dynamic assembly of TRPC1, STIM1, and Orai1 in a ternary complex in the ER-PM junctional domains, which is required for the activation of both Orai1 as well as TRPC1 channels. The TRPC1–STIM1–Orai1 complex, associated with SOCE, can be detected in HSG cells (Ong et al. 2007), mouse pulmonary arterial smooth muscle cells (Ng et al. 2009), human parathyroid (Lu et al. 2010), human liver cell (Zhang et al. 2010), and rat kidney fibroblast (Almirza et al. 2012). Assembly of this complex is mediated via STIM1, as knockdown of STIM1 prevents clustering of TRPC1 with Orai1. Knockdown of TRPC1 results in attenuation of function, while knockdown of Orai1 or STIM1 results in complete loss of SOCE. Furthermore, overexpression of pore-deficient, dominant-negative mutants of Orai1 (R91W, E106Q) abrogate Ca2+ entry due to TRPC1-STIM1 (Cheng et al. 2008; Ong et al. 2007). The exact mechanism by which Orai1 determines TRPC function has been a matter of much debate. It was suggested that Orai1 can physically interact with the C- and N-termini of both TRPC3 and TRPC6 channels and modulate channel sensitivity to store depletion and STIM1 (Liao et al. 2007). Hence, these investigators proposed that the endogenous SOCE channel pore is contributed by TRPC channels with Orai1 functioning as the regulatory subunit. Alternatively, TRPC channels have been proposed to modify Orai1 function.
The key question of whether TRPC and Orai1 contribute to a single channel pore (formation of a heteromeric TRPC + Orai1 channel) or are two distinct channels which independently contribute to SOCE has been resolved recently for TRPC1 and TRPC5. In a cell line where endogenous TRPC1 contributes to SOCE, TRPC1 and Orai1 form two distinct channels: a relatively Ca2+-selective channel mediating ISOC is composed of STIM1/TRPC1 and a highly Ca2+-selective channel mediating ICRAC is formed by STIM1/Orai1 (Cheng et al. 2011). The smaller conductance of ICRAC is masked by the larger STIM1/TRPC1-mediated current that gets activated under the same conditions. Hence, the ISOC attributed to STIM1/TRPC1 includes a small contribution from STIM1/Orai1 ICRAC. Further, native ICRAC is detected when TRPC1 channel function is suppressed in these cells by expression of the STIM1-KK/EE mutant, which can gate Orai1 but not TRPC1. More importantly, Ca2+ entry through STIM1/Orai1 facilitates TRPC1 channel trafficking and triggers TRPC1 insertion into the plasma membrane. Membrane insertion of TRPC is attenuated by removal of extracellular Ca2+, blocking ICRAC with 1 μM Gd3+, knockdown of Orai1 or overexpression of dominant-negative mutant of Orai1 (E106Q) that lacks a functional pore (Cheng et al. 2011). These data define the functional role of Orai1 and provide novel insights into the regulation and activation of TRPC1 in SOCE. Regulated surface insertion of TRPC1 by Orai1 can provide a rapid modulation and amplification of SOCE-facilitated Ca2+ signals that could selectively impact regulation of cell function (Cheng et al. 2013). Ca2+ entry via Orai1 has also been shown to facilitate TRPC5 activity (Gross et al. 2009). In this case, Ca2+ coming into the cell via Orai1 directly activates the TRPC5 channel. Detailed studies have not been done along these lines for other TRPCs to either demonstrate or rule out a secondary effect of Orai1 on channel function. It is important to note that heterologous expression might not yield similar data to that with endogenous channels, especially when several molecular components and regulatory mechanisms concertedly determine channel function.
5 Modulation of TRPC Channels by Membrane Trafficking
Localization of TRPC channels in specific plasma membrane microdomains allows the generation of precise intracellular Ca2+ signals that modulate downstream signaling events and consequent cell functions. The amplitude and duration of intracellular Ca2+ signals can be varied by regulating Ca2+ influx via TRPC channels, which can be enhanced by increasing the number of active channels at the cell surface either by driving channel trafficking to the plasma membrane or by prolonging channel retention at the cell surface. Major modes of regulating Ca2+ entry include constitutive and regulated vesicular trafficking mechanisms as well as the rates of protein synthesis and degradation. The constitutive and regulated trafficking processes determine the surface expression of TRPC channels by (1) increasing exocytosis and/or recycling to the plasma membrane or (2) reducing endocytosis and/or increasing channel retention in the plasma membrane.
5.1 TRPC1
Studies of the TRPC1 complex identified several interacting proteins that are involved in vesicle trafficking, membrane fusion, and cytoskeletal and actin rearrangement, such as clathrin, dynamin, Sec1, synapsin-2, Cav-1, and RhoA (Table 2). The TRPC1 signaling complex is localized in distinct cholesterol-rich plasma membrane domains known as lipid rafts. Disruption of lipid rafts with cholesterol-depleting agents like methyl-β-cyclodextrin (MβCD) decreased SOCE in salivary gland cells (Lockwich et al. 2000) and vascular smooth muscle cells (Bergdahl et al. 2003), suggesting lipid raft integrity is a prerequisite for TRPC1 localization and function. Cav-1 is a cholesterol-binding protein found within the caveolae, which are caveolin-containing lipid rafts present in the plasma membrane. Cav-1 plays an important role in the trafficking and function of TRPC1 (Brazer et al. 2003; Kwiatek et al. 2006; Lockwich et al. 2000; Pani et al. 2009, 2012). The present model proposes that Cav-1 functions as a scaffolding protein that facilitates assembly of the TRPC1 signaling complex and acts synergistically with Orai1 and STIM1 to regulate TRPC1 channel activity (Ong and Ambudkar 2012; Pani et al. 2009). In resting cells, TRPC1 is controlled by constitutive trafficking mechanisms. Following trafficking to the cell periphery, TRPC1 associates with Cav-1 but remains inactive and does not get inserted into the plasma membrane. When cells are stimulated by physiological agonists and the ER-Ca2+ stores are depleted, STIM1 translocates to the plasma membrane and activates the Orai1 channel. The Orai1-mediated Ca2+ influx drives the recruitment of TRPC1 into the plasma membrane. TRPC1 dissociates from Cav-1 and interacts with and is activated by STIM1. Dissociation of TRPC1 from Cav-1 is an essential step in the activation of TRPC1 by STIM1 since C-terminal684KK685 residues of STIM1 responsible for gating TRPC1 also releases the channel from Cav-1 (Pani et al. 2009; Zeng et al. 2008). In addition to Cav-1, Homer1 also interacts with TRPC1 in the C-terminus (aa 644–650), a region that lies just upstream of the STIM1-gating site (aa 639–640). Homer1 forms a dynamic complex with TRPC1 and IP3R. Following cell stimulation, the TRPC1/Homer1/IP3R complex disassembles, resulting in channel activation.
Local changes in the cytoskeleton or microtubules also contribute to the trafficking of TRPC1 (Bollimuntha et al. 2005a; Mehta et al. 2003). In retinal epithelial cells, β-tubulin has been shown to interact with TRPC1 and to be required for channel translocation to the plasma membrane (Bollimuntha et al. 2005a). RhoA, a monomeric GTPase protein responsible for actin cytoskeleton dynamics, associates with TRPC1 and IP3R in endothelial cells following stimulation with thrombin. Assembly of the TRPC1/IP3R complex, as well as trafficking to the plasma membrane, is dependent of RhoA and actin polymerization since SOCE is attenuated following treatment with C3 transferase protein that inactivates Rho or expression of a Rho dominant mutant (Mehta et al. 2003). Enkurin, a CaM-binding protein, interacts with TRPC1 and TRPC5 in sperm and has been suggested to function as an adaptor protein that tethers signaling proteins to TRPC channels (Sutton et al. 2004). Proteins involved in vesicle docking and fusion have also been reported to interact with TRPC1 and regulate channel activity. Nevertheless, the relevance of these various components in the intracellular trafficking of TRPC1 has yet to be identified.
5.2 TRPC3
As described earlier for TRPC1, the interactions of TRPC3 with several proteins are vital for its proper trafficking and cellular localization. These include PLCγ (van Rossum et al. 2005), Cav-1 (Lockwich et al. 2001), VAMP2 (Singh et al. 2004), RFN24 (Lussier et al. 2008), and Homer1 (Kim et al. 2006a). Surface expression of the TRPC3 channel requires interaction with PLCγ and PIP2, which anchors the channel in the plasma membrane (van Rossum et al. 2005). Homer1 has been reported to stabilize the interaction between TRPC3 and IP3R, determining the rate of TRPC3 translocation to and retrieval from the plasma membrane (Kim et al. 2006a; Kiselyov et al. 2007). Both Homer1 and junctate may function synergistically to facilitate the interaction between TRPC3 and IP3R which leads to channel activation. It is possible that the components involved in TRPC3 trafficking depend on the cell type and the spatial constraints within the cell.
Cell surface expression of TRPC3 is regulated by VAMP2-mediated fusion of mobile intracellular vesicles containing TRPC3 with the plasma membrane. Expression of TRPC3 in the plasma membrane increases following stimulation with carbachol, and this increase is abolished by treatment with tetanus toxin, which inhibits VAMP2 activity (Singh et al. 2004). Likewise, status of the actin cytoskeleton has also been reported to affect TRPC3 localization and function. Conditions that result in enhancement or stabilization of the cortical actin layer, such as treatment with jasplakinolide or calyculin A, promote internalization of TRPC3 signaling complex with a consequent decrease of TRPC3 function (Lockwich et al. 2001). TRPC3-interacting proteins may also influence the trafficking and surface expression of the channel. These include clathrin, dynamin, AP-2, syntaxin, synaptotagmin-1 (Lockwich et al. 2008), MxA (Lussier et al. 2005), and RACK1 (Bandyopadhyay et al. 2008) (Table 2). Additional studies are required to resolve the role of the TRPC3-interacting proteins involved in constitutive and regulated trafficking of the channel.
5.3 TRPC4
Although several studies have reported the association of TRPC4 with scaffolding and trafficking proteins (Table 2), the mechanisms regulating TRPC4 localization in the plasma membrane have not been fully elucidated. A dynamic interplay between tyrosine kinases, TRPC4, and NHERF regulates surface expression and activation of TRPC4 channels (Tang et al. 2000). The protein tyrosine kinase, fyn, phosphorylates TRPC4 following stimulation by the epidermal growth factor (EGF), increasing its interaction with NHERF, as well as its insertion into the plasma membrane (Odell et al. 2005). As mentioned above, TRPC4 forms a heteromeric complex with TRPC1 to mediate SOCE in endothelial cells. Loss of Cav-1 impairs surface expression of both TRPC4 and TRPC1, significantly reduces association of the heteromeric complex with IP3R, and inhibits agonist-induced Ca2+ entry in these cells. Hence, Cav-1 is proposed to function as a scaffold that facilitates the interactions between TRPC4, TRPC1, and IP3R.
5.4 TRPC5
Proteomic analysis of TRPC5-binding partners revealed the interactions of TRPC5 with proteins involved in vesicle trafficking and scaffolding (Table 2), such as dynamin, clathrin, AP-2 (Goel et al. 2005), and MxA (Lussier et al. 2005). Interaction of TRPC5 with the exocyst component protein, stathmin 2, targets homomeric channels to the growth cone of hippocampal neurons (Greka et al. 2003). In resting neuronal cells, TRPC5 is localized in intracellular vesicles close to the plasma membrane. Following stimulation with growth factors, TRPC5-containing vesicles are rapidly translocated and inserted to the plasma membrane, thereby increasing channel function constitutively. Trafficking of TRPC5 and insertion into the plasma membrane requires phosphatidylinositide 3-kinase (PI(3)K), Rac1, and phosphatidylinositol 4-phosphate 5-kinase (PIP(5)K). Interestingly, Rac1 initiates the insertion of homomeric TRPC5 but not the heteromeric TRPC1 + TRPC5 channels into the plasma membrane. This may be due to homomeric channels being localized in the growth cones to modulate elongation, whereas heteromeric channels are localized in the neurites (Bezzerides et al. 2004). It is also shown that TRPC5 participates in a molecular complex with Rac1 in fibroblasts and kidney podocytes and Ca2+ influx mediated by TRPC5 activates Rac1 (Tian et al. 2010). In aggregate, these studies show that components of the TRPC5 signaling complex determine its physiological function by influencing channel trafficking, localization, and activation.
5.5 TRPC6
There is a paucity of information on the proteins that interact with TRPC6 and regulate its trafficking to and localization in the plasma membrane (Table 2). Surface expression of TRPC6 is enhanced following cell stimulation by muscarinic receptor agonists or passive depletion of the ER-Ca2+ stores by thapsigargin (Cayouette et al. 2004). The GTPases, Rab9 and Rab11, have been shown to regulate the intracellular trafficking of TRPC6 in HeLa cells (Cayouette et al. 2010). In cells cotransfected with Rab9, TRPC6 shows a diffuse localization through the cell as well as partial colocalization with Rab9 containing vesicles. However, when Rab11 is overexpressed, TRPC6 is predominantly present at the cell periphery. Surface expression of TRPC6, as well as the channel activity, increases following the expression of a dominant-negative mutant of Rab9 (S21N) and Rab11, whereas channel activity decreases when dominant-negative mutant of Rab11 (S25N) is expressed. In aggregate, these data suggest that the intracellular trafficking of TRPC6 is through early endosomes and late endosomes, where the channel interacts with Rab9-containing vesicles and the channel is translocated to the plasma membrane via Rab11-containing vesicles (Cayouette et al. 2010). PI(3)K and PTEN have also been reported to regulate the trafficking and activation of TRPC6 channels. PTEN-dependent inhibition of PI(3)K reduced translocation of TRPC6 to the plasma membrane, as well as TRPC6-mediated Ca2+ influx in T6.11 cells. Previous studies have reported the interaction of TRPC6 with other proteins that are involved in vesicle trafficking, such as MxA (Lussier et al. 2005), RhoA (Tian et al. 2010), syntaxin (Bandyopadhyay et al. 2005), clathrin, and dynamin (Goel et al. 2005). MxA (which also interacts with other TRPCs except TRPC2) has been shown to modulate TRPC6-mediated Ca2+ entry in response to cell stimulation. The importance of such interactions in modulating surface expression and activity of TRPC6 remain to be fully delineated in future studies.
5.6 TRPC2 and TRPC7
There is relatively less information regarding the protein interactions and trafficking of TRPC2 and TRPC7. Similar to other TRPC channels, TRPC2 interacts with enkurin (Sutton et al. 2004) and Homer (Yuan et al. 2003). It has also been shown that the chaperone receptor-transporting protein 1 (RTP1) regulates the surface expression and channel activity of TRPC2 in HEK 293 cells. In cells cotransfected with RTP1, the surface expression of TRPC2, as well as the channel activity, is increased relative to cells expressing TRPC2 alone (Mast et al. 2010). A previous study demonstrates that TRPC7 interacts with MxA, a member of the dynamin superfamily (Lussier et al. 2005).
Conclusion
In summary, TRPC channels are regulated downstream from receptor-coupled PLC activation. These channels contribute to a wide variety of cellular function. Loss or gain of channel function has resulted in aberrant physiology in human and mouse. The physiological function and regulation of TRPC channels are influenced by their physical and functional interactions with numerous channels and proteins involved in the signaling, scaffolding, and trafficking processes. Further studies are required to delineate the exact steps involved in assembling TRPC channels with their accessory proteins to form functional signaling complexes in discrete ER-PM junctional regions. Understanding the various modes and mechanisms involved in TRPC channel function can provide potentially important targets for treatment of a number of diseases.
References
Adebiyi A, Thomas-Gatewood CM, Leo MD, Kidd MW, Neeb ZP, Jaggar JH (2012) An elevation in physical coupling of type 1 inositol 1,4,5-trisphosphate (IP3) receptors to transient receptor potential 3 (TRPC3) channels constricts mesenteric arteries in genetic hypertension. Hypertension 60:1213–1219
Almirza WH, Peters PH, van Zoelen EJ, Theuvenet AP (2012) Role of Trpc channels, Stim1 and Orai1 in PGF(2alpha)-induced calcium signaling in NRK fibroblasts. Cell Calcium 51:12–21
Alvarez J, Coulombe A, Cazorla O, Ugur M, Rauzier JM, Magyar J, Mathieu EL, Boulay G, Souto R, Bideaux P, Salazar G, Rassendren F, Lacampagne A, Fauconnier J, Vassort G (2008) ATP/UTP activate cation-permeable channels with TRPC3/7 properties in rat cardiomyocytes. Am J Physiol Heart Circ Physiol 295:H21–H28
Ambudkar IS (2009) Unraveling smooth muscle contraction: the TRP link. Gastroenterology 137:1211–1214
Ambudkar IS, Ong HL (2007) Organization and function of TRPC channelosomes. Pflugers Arch 455:187–200
Ambudkar IS, Bandyopadhyay BC, Liu X, Lockwich TP, Paria B, Ong HL (2006) Functional organization of TRPC-Ca2+ channels and regulation of calcium microdomains. Cell Calcium 40:495–504
Ambudkar IS, Ong HL, Liu X, Bandyopadhyay BC, Cheng KT (2007) TRPC1: the link between functionally distinct store-operated calcium channels. Cell Calcium 42:213–223
Antigny F, Girardin N, Frieden M (2012) Transient receptor potential canonical channels are required for in vitro endothelial tube formation. J Biol Chem 287:5917–5927
Antoniotti S, Pla AF, Barral S, Scalabrino O, Munaron L, Lovisolo D (2006) Interaction between TRPC channel subunits in endothelial cells. J Recept Signal Transduct Res 26:225–240
Balzer M, Lintschinger B, Groschner K (1999) Evidence for a role of Trp proteins in the oxidative stress-induced membrane conductances of porcine aortic endothelial cells. Cardiovasc Res 42:543–549
Bandyopadhyay BC, Swaim WD, Liu X, Redman RS, Patterson RL, Ambudkar IS (2005) Apical localization of a functional TRPC3/TRPC6-Ca2+-signaling complex in polarized epithelial cells. Role in apical Ca2+ influx. J Biol Chem 280:12908–12916
Bandyopadhyay BC, Ong HL, Lockwich TP, Liu X, Paria BC, Singh BB, Ambudkar IS (2008) TRPC3 controls agonist-stimulated intracellular Ca2+ release by mediating the interaction between inositol 1,4,5-trisphosphate receptor and RACK1. J Biol Chem 283:32821–32830
Bandyopadhyay BC, Swaim WD, Sarkar A, Liu X, Ambudkar IS (2012) Extracellular Ca2+ sensing in salivary ductal cells. J Biol Chem 287:30305–30316
Beech DJ (2005) TRPC1: store-operated channel and more. Pflugers Arch 451:53–60
Bergdahl A, Gomez MF, Dreja K, Xu SZ, Adner M, Beech DJ, Broman J, Hellstrand P, Sward K (2003) Cholesterol depletion impairs vascular reactivity to endothelin-1 by reducing store-operated Ca2+ entry dependent on TRPC1. Circ Res 93:839–847
Bezzerides VJ, Ramsey IS, Kotecha S, Greka A, Clapham DE (2004) Rapid vesicular translocation and insertion of TRP channels. Nat Cell Biol 6:709–720
Blair NT, Kaczmarek JS, Clapham DE (2009) Intracellular calcium strongly potentiates agonist-activated TRPC5 channels. J Gen Physiol 133:525–546
Bollimuntha S, Cornatzer E, Singh BB (2005a) Plasma membrane localization and function of TRPC1 is dependent on its interaction with beta-tubulin in retinal epithelium cells. Vis Neurosci 22:163–170
Bollimuntha S, Singh BB, Shavali S, Sharma SK, Ebadi M (2005b) TRPC1-mediated inhibition of 1-methyl-4-phenylpyridinium ion neurotoxicity in human SH-SY5Y neuroblastoma cells. J Biol Chem 280:2132–2140
Bomben VC, Turner KL, Barclay TT, Sontheimer H (2011) Transient receptor potential canonical channels are essential for chemotactic migration of human malignant gliomas. J Cell Physiol 226:1879–1888
Brazer SC, Singh BB, Liu X, Swaim W, Ambudkar IS (2003) Caveolin-1 contributes to assembly of store-operated Ca influx channels by regulating plasma membrane localization of TRPC1. J Biol Chem 278:27208–27215
Bush EW, Hood DB, Papst PJ, Chapo JA, Minobe W, Bristow MR, Olson EN, McKinsey TA (2006) Canonical transient receptor potential channels promote cardiomyocyte hypertrophy through activation of calcineurin signaling. J Biol Chem 281:33487–33496
Cayouette S, Lussier MP, Mathieu EL, Bousquet SM, Boulay G (2004) Exocytotic insertion of TRPC6 channel into the plasma membrane upon Gq protein-coupled receptor activation. J Biol Chem 279:7241–7246
Cayouette S, Bousquet SM, Francoeur N, Dupre E, Monet M, Gagnon H, Guedri YB, Lavoie C, Boulay G (2010) Involvement of Rab9 and Rab11 in the intracellular trafficking of TRPC6. Biochim Biophys Acta 1803:805–812
Chen J, Crossland RF, Noorani MM, Marrelli SP (2009) Inhibition of TRPC1/TRPC3 by PKG contributes to NO-mediated vasorelaxation. Am J Physiol Heart Circ Physiol 297:H417–H424
Cheng KT, Liu X, Ong HL, Ambudkar IS (2008) Functional requirement for Orai1 in store-operated TRPC1-STIM1 channels. J Biol Chem 283:12935–12940
Cheng KT, Liu X, Ong HL, Swaim W, Ambudkar IS (2011) Local Ca2+ entry via Orai1 regulates plasma membrane recruitment of TRPC1 and controls cytosolic Ca2+ signals required for specific cell functions. PLoS Biol 9:e1001025
Cheng KT, Ong HL, Liu X, Ambudkar IS (2013) Contribution and regulation of TRPC channels in store-operated Ca2+ entry. In: Prakriya M (ed) Store-operated calcium channels, vol 71. Elsevier, Amterdam, pp 150–179
Cheung KK, Yeung SS, Au SW, Lam LS, Dai ZQ, Li YH, Yeung EW (2011) Expression and association of TRPC1 with TRPC3 during skeletal myogenesis. Muscle Nerve 44:358–365
Chu X, Tong Q, Cheung JY, Wozney J, Conrad K, Mazack V, Zhang W, Stahl R, Barber DL, Miller BA (2004) Interaction of TRPC2 and TRPC6 in erythropoietin modulation of calcium influx. J Biol Chem 279:10514–10522
Cioffi DL, Wu S, Alexeyev M, Goodman SR, Zhu MX, Stevens T (2005) Activation of the endothelial store-operated ISOC Ca2+ channel requires interaction of protein 4.1 with TRPC4. Circ Res 97:1164–1172
Cuddapah VA, Turner KL, Sontheimer H (2013) Calcium entry via TRPC1 channels activates chloride currents in human glioma cells. Cell Calcium 53:187–194
Dibattista M, Amjad A, Maurya DK, Sagheddu C, Montani G, Tirindelli R, Menini A (2012) Calcium-activated chloride channels in the apical region of mouse vomeronasal sensory neurons. J Gen Physiol 140:3–15
Dietrich A, Kalwa H, Rost BR, Gudermann T (2005) The diacylgylcerol-sensitive TRPC3/6/7 subfamily of cation channels: functional characterization and physiological relevance. Pflugers Arch 451:72–80
Fiorio Pla A, Maric D, Brazer SC, Giacobini P, Liu X, Chang YH, Ambudkar IS, Barker JL (2005) Canonical transient receptor potential 1 plays a role in basic fibroblast growth factor (bFGF)/FGF receptor-1-induced Ca2+ entry and embryonic rat neural stem cell proliferation. J Neurosci 25:2687–2701
Gervasio OL, Whitehead NP, Yeung EW, Phillips WD, Allen DG (2008) TRPC1 binds to caveolin-3 and is regulated by Src kinase – role in Duchenne muscular dystrophy. J Cell Sci 121:2246–2255
Goel M, Sinkins WG, Schilling WP (2002) Selective association of TRPC channel subunits in rat brain synaptosomes. J Biol Chem 277:48303–48310
Goel M, Sinkins W, Keightley A, Kinter M, Schilling WP (2005) Proteomic analysis of TRPC5- and TRPC6-binding partners reveals interaction with the plasmalemmal Na+/K+-ATPase. Pflugers Arch 451:87–98
Greka A, Navarro B, Oancea E, Duggan A, Clapham DE (2003) TRPC5 is a regulator of hippocampal neurite length and growth cone morphology. Nat Neurosci 6:837–845
Gross SA, Guzman GA, Wissenbach U, Philipp SE, Zhu MX, Bruns D, Cavalie A (2009) TRPC5 is a Ca2+-activated channel functionally coupled to Ca2+-selective ion channels. J Biol Chem 284:34423–34432
Harada M, Luo X, Qi XY, Tadevosyan A, Maguy A, Ordog B, Ledoux J, Kato T, Naud P, Voigt N, Shi Y, Kamiya K, Murohara T, Kodama I, Tardif JC, Schotten U, Van Wagoner DR, Dobrev D, Nattel S (2012) Transient receptor potential canonical-3 channel-dependent fibroblast regulation in a trial fibrillation. Circulation 126:2051–2064
Heo DK, Chung WY, Park HW, Yuan JP, Lee MG, Kim JY (2012) Opposite regulatory effects of TRPC1 and TRPC5 on neurite outgrowth in PC12 cells. Cell Signal 24:899–906
Hirschler-Laszkiewicz I, Tong Q, Conrad K, Zhang W, Flint WW, Barber AJ, Barber DL, Cheung JY, Miller BA (2009) TRPC3 activation by erythropoietin is modulated by TRPC6. J Biol Chem 284:4567–4581
Hisatsune C, Kuroda Y, Nakamura K, Inoue T, Nakamura T, Michikawa T, Mizutani A, Mikoshiba K (2004) Regulation of TRPC6 channel activity by tyrosine phosphorylation. J Biol Chem 279:18887–18894
Hofmann T, Schaefer M, Schultz G, Gudermann T (2002) Subunit composition of mammalian transient receptor potential channels in living cells. Proc Natl Acad Sci U S A 99:7461–7466
Hogan PG, Lewis RS, Rao A (2010) Molecular basis of calcium signaling in lymphocytes: STIM and ORAI. Annu Rev Immunol 28:491–533
Hoth M, Penner R (1992) Depletion of intracellular calcium stores activates a calcium current in mast cells. Nature 355:353–356
Hoth M, Fasolato C, Penner R (1993) Ion channels and calcium signaling in mast cells. Ann NY Acad Sci 707:198–209
Hou X, Pedi L, Diver MM, Long SB (2012) Crystal structure of the calcium release-activated calcium channel Orai. Science 338:1308–1313
Hu G, Oboukhova EA, Kumar S, Sturek M, Obukhov AG (2009) Canonical transient receptor potential channels expression is elevated in a porcine model of metabolic syndrome. Mol Endocrinol 23:689–699
Huang GN, Zeng W, Kim JY, Yuan JP, Han L, Muallem S, Worley PF (2006) STIM1 carboxyl-terminus activates native SOC, I(crac) and TRPC1 channels. Nat Cell Biol 8:1003–1010
Hui H, McHugh D, Hannan M, Zeng F, Xu SZ, Khan SU, Levenson R, Beech DJ, Weiss JL (2006) Calcium-sensing mechanism in TRPC5 channels contributing to retardation of neurite outgrowth. J Physiol 572:165–172
Ji W, Xu P, Li Z, Lu J, Liu L, Zhan Y, Chen Y, Hille B, Xu T, Chen L (2008) Functional stoichiometry of the unitary calcium-release-activated calcium channel. Proc Natl Acad Sci U S A 105:13668–13673
Ju M, Shi J, Saleh SN, Albert AP, Large WA (2010) Ins(1,4,5)P3 interacts with PIP2 to regulate activation of TRPC6/C7 channels by diacylglycerol in native vascular myocytes. J Physiol 588:1419–1433
Kim JY, Saffen D (2005) Activation of M1 muscarinic acetylcholine receptors stimulates the formation of a multiprotein complex centered on TRPC6 channels. J Biol Chem 280:32035–32047
Kim JY, Zeng W, Kiselyov K, Yuan JP, Dehoff MH, Mikoshiba K, Worley PF, Muallem S (2006a) Homer 1 mediates store- and inositol 1,4,5-trisphosphate receptor-dependent translocation and retrieval of TRPC3 to the plasma membrane. J Biol Chem 281:32540–32549
Kim MT, Kim BJ, Lee JH, Kwon SC, Yeon DS, Yang DK, So I, Kim KW (2006b) Involvement of calmodulin and myosin light chain kinase in activation of mTRPC5 expressed in HEK cells. Am J Physiol Cell Physiol 290:C1031–C1040
Kiselyov K, Mignery GA, Zhu MX, Muallem S (1999) The N-terminal domain of the IP3 receptor gates store-operated hTrp3 channels. Mol Cell 4:423–429
Kiselyov K, Shin DM, Kim JY, Yuan JP, Muallem S (2007) TRPC channels: interacting proteins. In: Flockerzi V, Nilius B (eds) Transient receptor potential (TRP) channels, vol 179. Springer, New York, NY, pp 559–574
Kitajima N, Watanabe K, Morimoto S, Sato Y, Kiyonaka S, Hoshijima M, Ikeda Y, Nakaya M, Ide T, Mori Y, Kurose H, Nishida M (2011) TRPC3-mediated Ca2+ influx contributes to Rac1-mediated production of reactive oxygen species in MLP-deficient mouse hearts. Biochem Biophys Res Commun 409:108–113
Kwiatek AM, Minshall RD, Cool DR, Skidgel RA, Malik AB, Tiruppathi C (2006) Caveolin-1 regulates store-operated Ca2+ influx by binding of its scaffolding domain to transient receptor potential channel-1 in endothelial cells. Mol Pharmacol 70:1174–1183
Lee YM, Kim BJ, Kim HJ, Yang SK, Zhu MH, Lee KP, So I, Kim KW (2003) TRPC5 as a candidate for the nonselective cation channel activated by muscarinic stimulation in murine stomach. Am J Physiol 284:G604–G616
Lee KP, Yuan JP, Hong JH, So I, Worley PF, Muallem S (2010) An endoplasmic reticulum/plasma membrane junction: STIM1/Orai1/TRPCs. FEBS Lett 584:2022–2027
Li Y, Jia YC, Cui K, Li N, Zheng ZY, Wang YZ, Yuan XB (2005) Essential role of TRPC channels in the guidance of nerve growth cones by brain-derived neurotrophic factor. Nature 434:894–898
Li M, Chen C, Zhou Z, Xu S, Yu Z (2012a) A TRPC1-mediated increase in store-operated Ca2+ entry is required for the proliferation of adult hippocampal neural progenitor cells. Cell Calcium 51:486–496
Li W, Calfa G, Larimore J, Pozzo-Miller L (2012b) Activity-dependent BDNF release and TRPC signaling is impaired in hippocampal neurons of Mecp2 mutant mice. Proc Natl Acad Sci U S A 109:17087–17092
Liao Y, Erxleben C, Yildirim E, Abramowitz J, Armstrong DL, Birnbaumer L (2007) Orai proteins interact with TRPC channels and confer responsiveness to store depletion. Proc Natl Acad Sci U S A 104:4682–4687
Liman ER, Corey DP, Dulac C (1999) TRP2: a candidate transduction channel for mammalian pheromone sensory signalling. Proc Natl Acad Sci U S A 96:5791–5796
Liou J, Kim ML, Heo WD, Jones JT, Myers JW, Ferrell JE Jr, Meyer T (2005) STIM is a Ca2+ sensor essential for Ca2+-store-depletion-triggered Ca2+ influx. Curr Biol 15:1235–1241
Liu X, Singh BB, Ambudkar IS (2003) TRPC1 is required for functional store-operated Ca2+ channels. Role of acidic amino acid residues in the S5-S6 region. J Biol Chem 278:11337–11343
Liu X, Groschner K, Ambudkar IS (2004) Distinct Ca2+-permeable cation currents are activated by internal Ca2+-store depletion in RBL-2H3 cells and human salivary gland cells, HSG and HSY. J Membr Biol 200:93–104
Liu X, Bandyopadhyay BC, Singh BB, Groschner K, Ambudkar IS (2005) Molecular analysis of a store-operated and 2-acetyl-sn-glycerol-sensitive non-selective cation channel. Heteromeric assembly of TRPC1-TRPC3. J Biol Chem 280:21600–21606
Lockwich TP, Liu X, Singh BB, Jadlowiec J, Weiland S, Ambudkar IS (2000) Assembly of Trp1 in a signaling complex associated with caveolin-scaffolding lipid raft domains. J Biol Chem 275:11934–11942
Lockwich T, Singh BB, Liu X, Ambudkar IS (2001) Stabilization of cortical actin induces internalization of transient receptor potential 3 (Trp3)-associated caveolar Ca2+ signaling complex and loss of Ca2+ influx without disruption of Trp3-inositol trisphosphate receptor association. J Biol Chem 276:42401–42408
Lockwich T, Pant J, Makusky A, Jankowska-Stephens E, Kowalak JA, Markey SP, Ambudkar IS (2008) Analysis of TRPC3-interacting proteins by tandem mass spectrometry. J Proteome Res 7:979–989
Lu M, Branstrom R, Berglund E, Hoog A, Bjorklund P, Westin G, Larsson C, Farnebo LO, Forsberg L (2010) Expression and association of TRPC subtypes with Orai1 and STIM1 in human parathyroid. J Mol Endocrinol 44:285–294
Lussier MP, Cayouette S, Lepage PK, Bernier CL, Francoeur N, St-Hilaire M, Pinard M, Boulay G (2005) MxA, a member of the dynamin superfamily, interacts with the ankyrin-like repeat domain of TRPC. J Biol Chem 280:19393–19400
Lussier MP, Lepage PK, Bousquet SM, Boulay G (2008) RNF24, a new TRPC interacting protein, causes the intracellular retention of TRPC. Cell Calcium 43:432–443
Ma X, Cao J, Luo J, Nilius B, Huang Y, Ambudkar IS, Yao X (2010) Depletion of intracellular Ca2+ stores stimulates the translocation of vanilloid transient receptor potential 4-c1 heteromeric channels to the plasma membrane. Arterioscler Thromb Vasc Biol 30:2249–2255
Ma X, Cheng KT, Wong CO, O’Neil RG, Birnbaumer L, Ambudkar IS, Yao X (2011) Heteromeric TRPV4-C1 channels contribute to store-operated Ca2+ entry in vascular endothelial cells. Cell Calcium 50:502–509
Maruyama Y, Nakanishi Y, Walsh EJ, Wilson DP, Welsh DG, Cole WC (2006) Heteromultimeric TRPC6-TRPC7 channels contribute to arginine vasopressin-induced cation current of A7r5 vascular smooth muscle cells. Circ Res 98:1520–1527
Mast TG, Brann JH, Fadool DA (2010) The TRPC2 channel forms protein-protein interactions with Homer and RTP in the rat vomeronasal organ. BMC Neurosci 11:61
McGurk JS, Shim S, Kim JY, Wen Z, Song H, Ming GL (2011) Postsynaptic TRPC1 function contributes to BDNF-induced synaptic potentiation at the developing neuromuscular junction. J Neurosci 31:14754–14762
Mehta D, Ahmmed GU, Paria BC, Holinstat M, Voyno-Yasenetskaya T, Tiruppathi C, Minshall RD, Malik AB (2003) RhoA interaction with inositol 1,4,5-triphosphate receptor and transient receptor potential channel-1 regulates Ca2+ entry. J Biol Chem 278:33492–33500
Mery L, Magnino F, Schmidt K, Krause KH, Dufour J-F (2001) Alternative splice variants of hTrp4 differentially interact with the C-terminal portion of the inositol 1,4,5-trisphosphate receptors. FEBS Lett 487:377–383
Miehe S, Bieberstein A, Arnould I, Ihdene O, Rutten H, Strubing C (2010) The phospholipid-binding protein SESTD1 is a novel regulator of the transient receptor potential channels TRPC4 and TRPC5. J Biol Chem 285:12426–12434
Monet M, Francoeur N, Boulay G (2012) Involvement of phosphoinositide 3-kinase and PTEN protein in mechanism of activation of TRPC6 protein in vascular smooth muscle cells. J Biol Chem 287:17672–17681
Mukerji N, Damodaran TV, Winn MP (2007) TRPC6 and FSGS: the latest TRP channelopathy. Biochim Biophys Acta 1772:859–868
Murata T, Lin MI, Stan RV, Bauer PM, Yu J, Sessa WC (2007) Genetic evidence supporting caveolae microdomain regulation of calcium entry in endothelial cells. J Biol Chem 282:16631–16643
Nagamine K, Kudoh J, Minoshima S, Kawasaki K, Asakawa S, Ito F, Shimizu N (1998) Molecular cloning of a novel putative Ca2+ channel protein (TRPC7) highly expressed in brain. Genomics 54:124–131
Ng LC, McCormack MD, Airey JA, Singer CA, Keller PS, Shen XM, Hume JR (2009) TRPC1 and STIM1 mediate capacitative Ca2+ entry in mouse pulmonary arterial smooth muscle cells. J Physiol 587:2429–2442
Nilius B, Owsianik G (2010) Channelopathies converge on TRPV4. Nat Genet 42:98–100
Noorani MM, Noel RC, Marrelli SP (2011) Upregulated TRPC3 and downregulated TRPC1 channel expression during hypertension is associated with increased vascular contractility in rat. Front Physiol 2:42
Numaga T, Wakamori M, Mori Y (2007) Trpc7. In: Flockerzi V, Nilius B (eds) Transient receptor potential (TRP) channels. Springer, New York, NY, pp 143–151
Obukhov AG, Nowycky MC (2004) TRPC5 activation kinetics are modulated by the scaffolding protein ezrin/radixin/moesin-binding phosphoprotein-50 (EBP50). J Cell Physiol 201:227–235
Odell AF, Scott JL, Van Helden DF (2005) Epidermal growth factor induces tyrosine phosphorylation, membrane insertion, and activation of transient receptor potential channel 4. J Biol Chem 280:37974–37987
Ohta T, Morishita M, Mori Y, Ito S (2004) Ca2+ store-independent augmentation of [Ca2+]i responses to G-protein coupled receptor activation in recombinantly TRPC5-expressed rat pheochromocytoma (PC12) cells. Neurosci Lett 358:161–164
Ong HL, Ambudkar IS (2012) Role of lipid rafts in the regulation of store-operated Ca2+ channels. In: Levitan I, Barrantes F (eds) Cholesterol regulation of ion channels and receptors. Wiley, Hoboken, NJ, pp 69–90
Ong HL, Cheng KT, Liu X, Bandyopadhyay BC, Paria BC, Soboloff J, Pani B, Gwack Y, Srikanth S, Singh BB, Gill DL, Ambudkar IS (2007) Dynamic assembly of TRPC1-STIM1-Orai1 ternary complex is involved in store-operated calcium influx. Evidence for similarities in store-operated and calcium release-activated calcium channel components. J Biol Chem 282:9105–9116
Ong EC, Nesin V, Long CL, Bai CX, Guz JL, Ivanov IP, Abramowitz J, Birnbaumer L, Humphrey MB, Tsiokas L (2013) A TRPC1-dependent pathway regulates osteoclast formation and function. J Biol Chem 288:22219–22232
Owsianik G, Talavera K, Voets T, Nilius B (2006) Permeation and selectivity of TRP channels. Annu Rev Physiol 68:685–717
Pani B, Ong HL, Liu X, Rauser K, Ambudkar IS, Singh BB (2008) Lipid rafts determine clustering of STIM1 in endoplasmic reticulum-plasma membrane junctions and regulation of store-operated Ca2+ entry (SOCE). J Biol Chem 283:17333–17340
Pani B, Ong HL, Brazer SC, Liu X, Rauser K, Singh BB, Ambudkar IS (2009) Activation of TRPC1 by STIM1 in ER-PM microdomains involves release of the channel from its scaffold caveolin-1. Proc Natl Acad Sci U S A 106:20087–20092
Pani B, Liu X, Bollimuntha S, Cheng KT, Niesman IR, Zheng C, Achen VR, Patel HH, Ambudkar IS, Singh BB (2012) Impairment of TRPC1-STIM1 channel assembly and AQP5 translocation compromise agonist-stimulated fluid secretion in mice lacking caveolin1. J Cell Sci 126:667–675
Parekh AB, Penner R (1997) Store depletion and calcium influx. Physiol Rev 77:901–930
Parekh AB, Putney JW Jr (2005) Store-operated calcium channels. Physiol Rev 85:757–810
Paria BC, Vogel SM, Ahmmed GU, Alamgir S, Shroff J, Malik AB, Tiruppathi C (2004) Tumor necrosis factor-alpha-induced TRPC1 expression amplifies store-operated Ca2+ influx and endothelial permeability. Am J Physiol Lung Cell Mol Physiol 287:L1303–L1313
Park JY, Hwang EM, Yarishkin O, Seo JH, Kim E, Yoo J, Yi GS, Kim DG, Park N, Ha CM, La JH, Kang D, Han J, Oh U, Hong SG (2008) TRPM4b channel suppresses store-operated Ca2+ entry by a novel protein-protein interaction with the TRPC3 channel. Biochem Biophys Res Commun 368:677–683
Patterson RL, van Rossum DB, Ford DL, Hurt KJ, Bae SS, Suh P-G, Kurosaki T, Snyder SH, Gill DL (2002) Phospholipase C-γ is required for agonist-induced Ca2+ entry. Cell 111:529–541
Penna A, Demuro A, Yeromin AV, Zhang SL, Safrina O, Parker I, Cahalan MD (2008) The CRAC channel consists of a tetramer formed by Stim-induced dimerization of Orai dimers. Nature 456:116–120
Phelan KD, Shwe UT, Abramowitz J, Wu H, Rhee SW, Howell MD, Gottschall PE, Freichel M, Flockerzi V, Birnbaumer L, Zheng F (2013) Canonical transient receptor channel 5 (TRPC5) and TRPC1/4 contribute to seizure and excitotoxicity by distinct cellular mechanisms. Mol Pharmacol 83:429–438
Poteser M, Graziani A, Rosker C, Eder P, Derler I, Kahr H, Zhu MX, Romanin C, Groschner K (2006) TRPC3 and TRPC4 associate to form a redox-sensitive cation channel. Evidence for expression of native TRPC3-TRPC4 heteromeric channels in endothelial cells. J Biol Chem 281:13588–13595
Puram SV, Riccio A, Koirala S, Ikeuchi Y, Kim AH, Corfas G, Bonni A (2011) A TRPC5-regulated calcium signaling pathway controls dendrite patterning in the mammalian brain. Genes Dev 25:2659–2673
Putney JW (2005) Physiological mechanisms of TRPC activation. Pflugers Arch 451:29–34
Rao JN, Platoshyn O, Golovina VA, Liu L, Zou T, Marasa BS, Turner DJ, Yuan JX, Wang JY (2006) TRPC1 functions as a store-operated Ca2+ channel in intestinal epithelial cells and regulates early mucosal restitution after wounding. Am J Physiol Gastrointest Liver Physiol 290:G782–G792
Redondo PC, Harper AG, Salido GM, Pariente JA, Sage SO, Rosado JA (2004) A role for SNAP-25 but not VAMPs in store-mediated Ca2+ entry in human platelets. J Physiol 558:99–109
Redondo PC, Jardin I, Lopez JJ, Salido GM, Rosado JA (2008) Intracellular Ca2+ store depletion induces the formation of macromolecular complexes involving hTRPC1, hTRPC6, the type II IP3 receptor and SERCA3 in human platelets. Biochim Biophys Acta 1783:1163–1176
Reiser J, Polu KR, Moller CC, Kenlan P, Altintas MM, Wei C, Faul C, Herbert S, Villegas I, Avila-Casado C, McGee M, Sugimoto H, Brown D, Kalluri R, Mundel P, Smith PL, Clapham DE, Pollak MR (2005) TRPC6 is a glomerular slit diaphragm-associated channel required for normal renal function. Nat Genet 37:739–744
Riccio A, Li Y, Moon J, Kim KS, Smith KS, Rudolph U, Gapon S, Yao GL, Tsvetkov E, Rodig SJ, Van’t Veer A, Meloni EG, Carlezon WA Jr, Bolshakov VY, Clapham DE (2009) Essential role for TRPC5 in amygdala function and fear-related behavior. Cell 137:761–772
Roos J, DiGregorio PJ, Yeromin AV, Ohlsen K, Lioudyno M, Zhang S, Safrina O, Kozak JA, Wagner SL, Cahalan MD, Velicelebi G, Stauderman KA (2005) STIM1, an essential and conserved component of store-operated Ca2+ channel function. J Cell Biol 169:435–445
Sabourin J, Lamiche C, Vandebrouck A, Magaud C, Rivet J, Cognard C, Bourmeyster N, Constantin B (2009) Regulation of TRPC1 and TRPC4 cation channels requires an alpha1-syntrophin-dependent complex in skeletal mouse myotubes. J Biol Chem 284:36248–36261
Saleh SN, Albert AP, Peppiatt-Wildman CM, Large WA (2008) Diverse properties of store-operated TRPC channels activated by protein kinase C in vascular myocytes. J Physiol 586:2463–2476
Satoh S, Tanaka H, Ueda Y, Oyama J, Sugano M, Sumimoto H, Mori Y, Makino N (2007) Transient receptor potential (TRP) protein 7 acts as a G protein-activated Ca2+ channel mediating angiotensin II-induced myocardial apoptosis. Mol Cell Biochem 294:205–215
Schaefer M, Plant TD, Obukhov AG, Hofmann T, Gudermann T, Schultz G (2000) Receptor-mediated regulation of the nonselective cation channels TRPC4 and TRPC5. J Biol Chem 275:17517–17526
Schindl R, Frischauf I, Kahr H, Fritsch R, Krenn M, Derndl A, Vales E, Muik M, Derler I, Groschner K, Romanin C (2008) The first ankyrin-like repeat is the minimum indispensable key structure for functional assembly of homo- and heteromeric TRPC4/TRPC5 channels. Cell Calcium 43:260–269
Schindl R, Fritsch R, Jardin I, Frischauf I, Kahr H, Muik M, Riedl MC, Groschner K, Romanin C (2012) Canonical transient receptor potential (TRPC) 1 acts as a negative regulator for vanilloid TRPV6-mediated Ca2+ influx. J Biol Chem 287:35612–35620
Selvaraj S, Watt JA, Singh BB (2009) TRPC1 inhibits apoptotic cell degeneration induced by dopaminergic neurotoxin MPTP/MPP+. Cell Calcium 46:209–218
Selvaraj S, Sun Y, Watt JA, Wang S, Lei S, Birnbaumer L, Singh BB (2012) Neurotoxin-induced ER stress in mouse dopaminergic neurons involves downregulation of TRPC1 and inhibition of AKT/mTOR signaling. J Clin Invest 122:1354–1367
Shi J, Ju M, Abramowitz J, Large WA, Birnbaumer L, Albert AP (2012) TRPC1 proteins confer PKC and phosphoinositol activation on native heteromeric TRPC1/C5 channels in vascular smooth muscle: comparative study of wild-type and TRPC1-/- mice. FASEB J 26:409–419
Shimizu S, Yoshida T, Wakamori M, Ishii M, Okada T, Takahashi M, Seto M, Sakurada K, Kiuchi Y, Mori Y (2006) Ca2+-calmodulin-dependent myosin light chain kinase is essential for activation of TRPC5 channels expressed in HEK293 cells. J Physiol 570:219–235
Singh BB, Liu X, Tang J, Zhu MX, Ambudkar IS (2002) Calmodulin regulates Ca2+-dependent feedback inhibition of store-operated Ca2+ influx by interaction with a site in the C terminus of TrpC1. Mol Cell 9:739–750
Singh BB, Lockwich TP, Bandyopadhyay BC, Liu X, Bollimuntha S, Brazer SC, Combs C, Das S, Leenders AG, Sheng ZH, Knepper MA, Ambudkar SV, Ambudkar IS (2004) VAMP2-dependent exocytosis regulates plasma membrane insertion of TRPC3 channels and contributes to agonist-stimulated Ca2+ influx. Mol Cell 15:635–646
Song X, Zhao Y, Narcisse L, Duffy H, Kress Y, Lee S, Brosnan CF (2005) Canonical transient receptor potential channel 4 (TRPC4) co-localizes with the scaffolding protein ZO-1 in human fetal astrocytes in culture. Glia 49:418–429
Sours-Brothers S, Ding M, Graham S, Ma R (2009) Interaction between TRPC1/TRPC4 assembly and STIM1 contributes to store-operated Ca2+ entry in mesangial cells. Exp Biol Med 234:673–682
Stiber JA, Zhang ZS, Burch J, Eu JP, Zhang S, Truskey GA, Seth M, Yamaguchi N, Meissner G, Shah R, Worley PF, Williams RS, Rosenberg PB (2008) Mice lacking Homer 1 exhibit a skeletal myopathy characterized by abnormal transient receptor potential channel activity. Mol Cell Biol 28:2637–2647
Strubing C, Krapivinsky G, Krapivinsky L, Clapham DE (2001) TRPC1 and TRPC5 form a novel cation channels in mammalian brain. Neuron 29:645–655
Strubing C, Krapivinsky G, Krapivinsky L, Clapham DE (2003) Formation of novel TRPC channels by complex subunit interactions in embryonic brain. J Biol Chem 278:39014–39019
Sukumaran P, Lof C, Pulli I, Kemppainen K, Viitanen T, Tornquist K (2013) Significance of the transient receptor potential canonical 2 (TRPC2) channel in the regulation of rat thyroid FRTL-5 cell proliferation, migration, adhesion and invasion. Mol Cell Endocrinol 374:10–21
Sundivakkam PC, Kwiatek AM, Sharma TT, Minshall RD, Malik AB, Tiruppathi C (2009) Caveolin-1 scaffold domain interacts with TRPC1 and IP3R3 to regulate Ca2+ store release-induced Ca2+ entry in endothelial cells. Am J Physiol Cell Physiol 296:C403–C413
Sundivakkam PC, Freichel M, Singh V, Yuan JP, Vogel SM, Flockerzi V, Malik AB, Tiruppathi C (2012) The Ca2+ sensor stromal interaction molecule 1 (STIM1) is necessary and sufficient for the store-operated Ca2+ entry function of transient receptor potential canonical (TRPC) 1 and 4 channels in endothelial cells. Mol Pharmacol 81:510–526
Sutton KA, Jungnickel MK, Wang Y, Cullen K, Lambert S, Florman HM (2004) Enkurin is a novel calmodulin and TRPC channel binding protein in sperm. Dev Biol 274:426–435
Tang Y, Tang J, Chen Z, Trost C, Flockerzi V, Li M, Ramesh V, Zhu MX (2000) Association of mammalian Trp4 and phospholipase C isozymes with a PDZ domain-containing protein, NHERF. J Biol Chem 275:27559–27564
Tang J, Lin Y, Zhang Z, Tikunova S, Birnbaumer L, Zhu MX (2001) Identification of common binding sites for calmodulin and IP3 receptors on the carboxyl-termini of TRP channels. J Biol Chem 276:21303–21310
Thebault S, Flourakis M, Vanoverberghe K, Vandermoere F, Roudbaraki M, Lehen’kyi V, Slomianny C, Beck B, Mariot P, Bonnal JL, Mauroy B, Shuba Y, Capiod T, Skryma R, Prevarskaya N (2006) Differential role of transient receptor potential channels in Ca2+ entry and proliferation of prostate cancer epithelial cells. Cancer Res 66:2038–2047
Tian D, Jacobo SM, Billing D, Rozkalne A, Gage SD, Anagnostou T, Pavenstadt H, Hsu HH, Schlondorff J, Ramos A, Greka A (2010) Antagonistic regulation of actin dynamics and cell motility by TRPC5 and TRPC6 channels. Sci Signal 3:ra77
Tong Q, Chu X, Cheung JY, Conrad K, Stahl R, Barber DL, Mignery G, Miller BA (2004) Erythropoietin-modulated calcium influx through TRPC2 is mediated by phospholipase Cgamma and IP3R. Am J Physiol Cell Physiol 287:C1667–C1678
Torihashi S, Fujimoto T, Trost C, Nakayama S (2002) Calcium oscillation linked to pacemaking of interstitial cells of Cajal: requirement of calcium influx and localization of TRP4 in caveolae. J Biol Chem 277:19191–19197
Tsvilovskyy VV, Zholos AV, Aberle T, Philipp SE, Dietrich A, Zhu MX, Birnbaumer L, Freichel M, Flockerzi V (2009) Deletion of TRPC4 and TRPC6 in mice impairs smooth muscle contraction and intestinal motility in vivo. Gastroenterology 137:1415–1424
Tu CL, Chang W, Bikle DD (2005) Phospholipase cgamma1 is required for activation of store-operated channels in human keratinocytes. J Invest Dermatol 124:187–197
van Rossum DB, Patterson RL, Sharma S, Barrow RK, Kornberg M, Gill DL, Snyder SH (2005) Phospholipase Cgamma1 controls surface expression of TRPC3 through an intermolecular PH domain. Nature 434:99–104
Vannier B, Peyton M, Boulay G, Brown D, Qin N, Jiang MS, Zhu X, Birnbaumer L (1999) Mouse trp2, the homologue of the human trpc2 pseudogene, encodes mTrp2, a store depletion-activated capacitative Ca2+ entry channel. Proc Natl Acad Sci U S A 99:2060–2064
Venkatachalam K, Montell C (2007) TRP channels. Annu Rev Biochem 76:387–417
Viitanen TM, Sukumaran P, Lof C, Tornquist K (2013) Functional coupling of TRPC2 cation channels and the calcium-activated anion channels in rat thyroid cells: implications for iodide homeostasis. J Cell Physiol 228:814–823
Wenning AS, Neblung K, Strauss B, Wolfs MJ, Sappok A, Hoth M, Schwarz EC (2011) TRP expression pattern and the functional importance of TRPC3 in primary human T-cells. Biochim Biophys Acta 1813:412–423
Wes PD, Chevesich J, Jeromin A, Rosenberg C, Stetten S, Montell C (1995) TRPC1, a human homolog of a Drosophila store-operated channel. Proc Natl Acad Sci U S A 92:9652–9656
Williams IA, Allen DG (2007) Intracellular calcium handling in ventricular myocytes from mdx mice. Am J Physiol Heart Circ Physiol 292:H846–H855
Wissenbach U, Schroth G, Philipp S, Flockerzi V (1998) Structure and mRNA expression of a bovine trp homologue related to mammalian trp2 transcripts. FEBS Lett 429:61–66
Woo JS, Kim do H, Allen PD, Lee EH (2008) TRPC3-interacting triadic proteins in skeletal muscle. Biochem J 411:399–405
Woo JS, Cho CH, Kim do H, Lee EH (2010) TRPC3 cation channel plays an important role in proliferation and differentiation of skeletal muscle myoblasts. Exp Mol Med 42:614–627
Woodard GE, Lopez JJ, Jardin I, Salido GM, Rosado JA (2010) TRPC3 regulates agonist-stimulated Ca2+ mobilization by mediating the interaction between type I inositol 1,4,5-trisphosphate receptor, RACK1, and Orai1. J Biol Chem 285:8045–8053
Worley PF, Zeng W, Huang GN, Yuan JP, Kim JY, Lee MG, Muallem S (2007) TRPC channels as STIM1-regulated store-operated channels. Cell Calcium 42:205–211
Wu X, Zagranichnaya TK, Gurda GT, Eves EM, Villereal ML (2004) A TRPC1/TRPC3-mediated increase in store-operated calcium entry is required for differentiation of H19-7 hippocampal neuronal cells. J Biol Chem 279:43392–43402
Wu X, Eder P, Chang B, Molkentin JD (2010) TRPC channels are necessary mediators of pathologic cardiac hypertrophy. Proc Natl Acad Sci U S A 107:7000–7005
Xu XZ, Li HS, Guggino WB, Montell C (1997) Coassembly of TRP and TRPL produces a distinct store-operated conductance. Cell 89:1155–1164
Xu SZ, Muraki K, Zeng F, Li J, Sukumar P, Shah S, Dedman AM, Flemming PK, McHugh D, Naylor J, Cheong A, Bateson AN, Munsch CM, Porter KE, Beech DJ (2006) A sphingosine-1-phosphate-activated calcium channel controlling vascular smooth muscle cell motility. Circ Res 98:1381–1389
Yildirim E, Dietrich A, Birnbaumer L (2003) The mouse C-type transient receptor potential 2 (TRPC2) channel: alternative splicing and calmodulin binding to its N terminus. Proc Natl Acad Sci U S A 100:2220–2225
Yuan JP, Kiselyov K, Shin DM, Chen J, Shcheynikov N, Kang SH, Dehoff MH, Schwarz MK, Seeburg PH, Muallem S, Worley PF (2003) Homer binds TRPC family channels and is required for gating of TRPC1 by IP3 receptors. Cell 114:777–789
Yuan JP, Zeng W, Huang GN, Worley PF, Muallem S (2007) STIM1 heteromultimerizes TRPC channels to determine their function as store-operated channels. Nat Cell Biol 9:636–645
Yuan JP, Zeng W, Dorwart MR, Choi YJ, Worley PF, Muallem S (2009) SOAR and the polybasic STIM1 domains gate and regulate Orai channels. Nat Cell Biol 11:337–343
Yuasa K, Matsuda T, Tsuji A (2011) Functional regulation of transient receptor potential canonical 7 by cGMP-dependent protein kinase Ialpha. Cell Signal 23:1179–1187
Zagranichnaya TK, Wu X, Villereal ML (2005) Endogenous TRPC1, TRPC3, and TRPC7 proteins combine to form native store-operated channels in HEK-293 cells. J Biol Chem 280:29559–29569
Zeng W, Yuan JP, Kim MS, Choi YJ, Huang GN, Worley PF, Muallem S (2008) STIM1 gates TRPC channels, but not Orai1, by electrostatic interaction. Mol Cell 32:439–448
Zhang Z, Tang J, Tikunova S, Johnson JD, Chen Z, Qin N, Dietrich A, Stefani E, Birnbaumer L, Zhu MX (2001) Activation of Trp3 by inositol 1, 4, 5-trisphosphate receptors through displacement of inhibitory calmodulin from a common binding domain. Proc Natl Acad Sci U S A 98:3168–3173
Zhang ZY, Pan LJ, Zhang ZM (2010) Functional interactions among STIM1, Orai1 and TRPC1 on the activation of SOCs in HL-7702 cells. Amino Acids 39:195–204
Zhu X, Chu PB, Peyton M, Birnbaumer L (1995) Molecular cloning of a widely expressed human homologue for the Drosophila trp gene. FEBS Lett 373:193–198
Zhu X, Jiang M, Peyton M, Boulay G, Hurst R, Stefani E, Birnbaumer L (1996) trp, a novel mammalian gene family essential for agonist-activated capacitative Ca2+ entry. Cell 85:661–671
Zimmermann K, Lennerz JK, Hein A, Link AS, Kaczmarek JS, Delling M, Uysal S, Pfeifer JD, Riccio A, Clapham DE (2011) Transient receptor potential cation channel, subfamily C, member 5 (TRPC5) is a cold-transducer in the peripheral nervous system. Proc Natl Acad Sci U S A 108:18114–18119
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2014 Springer International Publishing Switzerland
About this chapter
Cite this chapter
Ong, H.L., de Souza, L.B., Cheng, K.T., Ambudkar, I.S. (2014). Physiological Functions and Regulation of TRPC Channels. In: Nilius, B., Flockerzi, V. (eds) Mammalian Transient Receptor Potential (TRP) Cation Channels. Handbook of Experimental Pharmacology, vol 223. Springer, Cham. https://doi.org/10.1007/978-3-319-05161-1_12
Download citation
DOI: https://doi.org/10.1007/978-3-319-05161-1_12
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-05160-4
Online ISBN: 978-3-319-05161-1
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)