Abstract
Transient receptor potential (TRP) proteins are involved in a large number of non-selective cation channels that are permeable to both monovalent and divalent cations. Two general classes of receptor-mediated Ca2+ entry has been proposed: one of then is conduced by receptor-operated Ca2+ channels (ROC), the second is mediated by channels activated by the emptying of intracellular Ca2+ stores (store-operated channels or SOC). TRP channels have been presented as subunits of both ROC and SOC, although the precise mechanism that regulates the participation of TRP proteins in these Ca2+ entry mechanisms remains unclear. Recently, TRPC proteins have been shown to associate with Orai1 and STIM1 in a dynamic ternary complex regulated by the occupation of membrane receptors in several cell models, which might play an important role in the function of TRPC proteins. The present review summarizes the current knowledge concerning the association of TRP proteins with Orai and STIM proteins and how this affects the participation of TRP proteins in store-operated or receptor-operated Ca2+ entry.
Access provided by Autonomous University of Puebla. Download chapter PDF
Similar content being viewed by others
Keywords
23.1 Introduction
Regulation of the changes in cytosolic Ca2+ concentration is a point of convergence of many signal transduction pathways and modulates a variety of cellular functions ranging from fertilization to cell death. Changes in cytosolic free Ca2+ concentration ([Ca2+]c), also known as Ca2+ signals, are characterized by sudden and transitory increases in the concentration of free calcium ions [1]. Cell-generated Ca2+ signals require both internal and external Ca2+ sources. In most cell types, the major internal Ca2+ store is the endoplasmic reticulum (ER)/sarcoplasmic reticulum, where Ca2+ is stored by SERCA (sarco/endoplasmic reticulum Ca2+-ATPase). Due to the finite amount of Ca2+ accumulated in the ER the entry of extracellular Ca2+ is necessary to achieve full activation of a number of cellular functions. Store-operated Ca2+ entry (SOCE), also known as capacitative Ca2+ entry, a process regulated by the filling state of the intracellular Ca2+ stores, is a major mechanism for Ca2+ entry in non-electrically excitable cells [2]. There is a body of evidence supporting an important role for SOCE in Ca2+ signalling and intracellular homeostasis under physiological conditions, such as supporting Ca2+ oscillations [3]. In addition, SOCE has been reported to be required for a number of cellular processes, including cell proliferation, muscle contraction, platelet aggregation and secretion [4, 5]. Finally, SOCE serves as a mechanism to allow ER Ca2+ refilling, necessary for protein synthesis and post-translational modifications [6].
The nature of the channels that conduct SOCE has been a matter of intense investigation and debate. Two types of store operated Ca2+ channels have been described so far, which, although show distinct biophysical properties, are activated by depletion of intracellular Ca2+ stores with agonists, inhibitors of SERCA and/or strong Ca2+ chelators. First of all, Ca2+ release-activated Ca2+-selective (CRAC) channels have been found and extensively described on the level of whole-cell current in a variety of non-excitable cells, including mast cells, Jurkat T-lymphocytes and RBL cells [7–9]. The current through CRAC channels (I CRAC) is non-voltage activated, inwardly rectifying, and selective for Ca2+ [10, 11]. While I CRAC was the first store-operated Ca2+ current identified, it is not the only store-operated current, and SOCE has also been reported to include a family of Ca2+-permeable channels, with different properties in different cell types known as SOC channels, which conduct the non-voltage activated, non-selective I SOC current of small, but resolvable 0.7-11 pS conductance [12]. SOC channels have been found and described on single channel and whole-cell current levels in different cell types [13–16]. The mammalian homologues of the Drosophila Transient Receptor Potential (TRP) channels were initially presented as candidates for the conduction of SOCE and, more recently, the protein Orai1 has been proposed to form the pore of the channel mediating I CRAC.
Despite intense investigations over the last two decades, the mechanisms of activation and the identity of the key molecular players conducting Ca2+ entry during SOCE have long remained elusive. However, in the last few years, the improvements of gene silencing protocols combined with high throughput platforms have provided important breakthroughs, especially with the identification of STIM1 (stromal interaction molecule 1) as the ER Ca2+ sensor and Orai1 as the pore-forming subunit of the archetypical capacitative channel, CRAC. STIM1 is a Ca2+-binding protein located both in intracellular membranes, including the ER, and the plasma membrane with a single transmembrane region and an EF-hand domain in the N-terminus. STIM1 located in the ER shows the EF-hand domain in the lumen of the ER, which, by following different experimental manoeuvres, has been suggested to function as a Ca2+ sensor that communicates the filling state of the Ca2+ stores to the plasma membrane Ca2+ permeable channels [17, 18]. In addition, plasma membrane-resident STIM1, which shows the EF-hand domain facing the extracellular medium, has been reported to modulate the function of the capacitative channels [19, 20], probably acting as an extracellular Ca2+ sensor.
The involvement of Orai1 in I CRAC has been identified by gene mapping in patients showing an inherited disorder called severe combined immune deficiency (SCID) syndrome attributed to loss of I CRAC, which results in extreme vulnerability to infectious diseases. The ORAI1 gene located on chromosome 12 has been found to be mutated in SCID patients, and I CRAC has been shown to be restored by expression of wild type Orai1 in T cells [21]. The role of Orai1 in I CRAC was confirmed in a whole-genome screen of Drosophila S2 cells by Feske and coworkers [21], with other groups reporting similar results at the same time [22, 23]. Orai1 is a small protein with four transmembrane domains and both N- and C-terminal tails located in the cytosol. The Orai1 protein has been demonstrated to form multimeric ion channel complexes in the plasma membrane [24–29].
In addition to their involvement in receptor-operated Ca2+ entry (ROCE), there is now considerable evidence supporting a role for TRP proteins in the conduction of Ca2+ entry during SOCE. Particular attention has been paid to members of the TRPC subfamily. Using different approaches, from overexpression of specific TRP proteins to knockdown of endogenous TRPs and pharmacological studies, it has been suggested that most of the TRPC proteins can be activated by Ca2+ store depletion [12, 30, 31]. Among TRP proteins, the role of TRPC1 in SOCE has been extensively investigated in different cell types. TRPC1 has been reported to be involved in SOCE by antisense experiments in human salivary glands [32] and vascular endothelial cells [33]. In support of this, antibodies directed to the pore-forming region of TRPC1 have been shown to reduce SOCE in vascular smooth muscle cells and human platelets [34, 35] and TRPC1-depleted myoblasts present a largely reduced SOCE [36]. Different TRPC associations appear to give rise to channels with distinct biophysical properties. In addition, association of TRPC proteins with STIM1 and Orai1 seems to play an important role in the participation of TRPCs in different mechanisms for Ca2+ entry in a number of cell types, although the association between these proteins still remains controversial and further studies are required to fully understand the process.
23.2 Transient Receptor Potential (TRP) Proteins: TRPCs
TRP proteins are ion channel subunits non-selective for monovalent and divalent cations, including Na+ and Ca2+ that were initially identified in the trp mutant of Drosophila. The light-sensitive current in Drosophila photoreceptors is conducted by two Ca2+-permeable channels encoded by the trp and trpl genes [37, 38]. The trp mutant is characterized by transient, rather than sustained, light-sensitive depolarization due to Na+ and Ca2+ influx [39]. Later on, Drosophila TRP channels were shown to be gated by diacylglycerol (DAG) or a metabolic byproduct, synergistically with phosphatidylinositol 4,5-bisphosphate (PIP2) depletion [40].
The identification of mammalian homologues of Drosophila TRP channels raised interest in TRP proteins as candidates for Ca2+ entry channels. The first mammalian TRP protein, TRPC1, was identified in 1995 in human [41, 42] and mouse [43]. Since their identification, a number of TRP proteins have been found, which are grouped into seven major subfamilies: four are closely related to Drosophila TRP (TRPC, TRPV, TRPA and TRPM), two more distantly related subfamilies (TRPP and TRPML), and finally the TRPN group expressed so far only in fish, flies and worms [44]. The canonical TRP (TRPC) subfamily comprises seven members (TRPC1–TRPC7, which, in turn, can be divided into four groups: TRPC1, TRPC2, TRPC3/6/7 and TRPC4/5), the vanilloid TRP subfamily (TRPV) consists of six members (TRPV1–TRPV6), the TRPA (ankyrin) subfamily includes only one mammalian member, TRPA1, and the melastatin TRP subfamily (TRPM) groups eight different channels (TRPM1–TRPM8). The TRPP (polycystin) and the TRPML (mucolipin) subfamilies include three channel members each, and finally, the TRPN has no mammalian members [45].
All members of the TRP family share a common architecture: they are proteins that contain six transmembrane domains, with different cytoplasmic N- and C-termini depending on the subfamily, and a pore loop region between the transmembrane domains 5 and 6 [46]. Many TRP proteins possess long N-terminal regions with several protein–protein interaction domains known as ankyrin repeats, a coiled coil region, and a putative caveolin-binding domain. On the other hand, the C-terminus includes the TRP signature motif (EWKFAR), a proline-rich motif and different functional regions that facilitate their interaction with calmodulin or inositol 1,4,5-trisphosphate (IP3) receptor [47–49]. For further information concerning the structure of TRP proteins the reader is referred to Chapter 1.
As reported above, most TRP channels are nonselective for monovalent and divalent cations with Ca2+:Na+ permeability ratios <10 [50]. There are a number of exceptions, such as TRPM4 and TRPM5, which are selective for monovalent cations, and TRPV5 and TRPV6, which have a Ca2+:Na+ permeability ratio > 100. Among the TRP channels expressed in mammals, the role of the TRPC subfamily members on agonist-evoked Ca2+ entry has focused much attention, and, therefore, this review present an overview of the mechanisms involved in the participation of TRPC in Ca2+ entry.
The TRPC members form Ca2+-permeable cation channels and have been presented as candidate subunits for the channels conducting both SOCE and ROCE [30, 35, 51–53]. By means of different experimental manoeuvres, from gene inactivation to gene expression silencing using siRNA or shRNA and the use of neutralizing antibodies, all the members of the TRPC family have been reported to be activated by store depletion or to be involved in SOCE both in excitable and non-excitable cells, including TRPC1 [32, 34, 35, 54], TRPC2 [55], TRPC3 [56, 57], TRPC4 [58, 59], TRPC5 [59, 60], TRPC6 [61–63] and TRPC7 [64]. However, the participation of TRPCs in SOCE depends on special circumstances, such as the expression level. Thus, at low expression levels TRPCs are activated by depletion of the intracellular Ca2+ stores, while at relatively high levels of expression TRPCs are not longer sensitive to store depletion but activated by phospholipase C (PLC) or its metabolites [56]. Furthermore, it has been reported that TRPC channels might participate in SOCE or ROCE in the same cell type depending on their mode of expression. In HEK-293 cells, TRPC7 is activated by PLC-stimulating agonists and not by Ca2+ store discharge when transiently expressed; in contrast, stably expressed TRPC7 gating can be regulated by either Ca2+ stores or PLC activation [64]. Although the reason for this phenomenon has not been determined it might be attributed to the association of TRPC proteins with regulatory subunits that confer store depletion or receptor sensitivity and then participation in SOCE or ROCE. The identification of STIM1 and Orai1 as essential components of SOCE may uncover the mechanism underlying the participation of TRPC subunits in SOCE or ROCE, as reported below.
23.3 STIM and Orai Proteins
Probably one of the most significant advances occurred in the last 5 years on the intracellular Ca2+ homeostasis has been, together with the determination of the structure of Orai, demonstrating that STIM1 is the ER sensor that report its Ca2+ filling state, essential for Ca2+ store depletion-triggered Ca2+ influx across de plasma membrane. Although two single transmembrane-spanning domain stromal interaction molecules with no known catalytic activity (human STIM1 and STIM2 containing 685 and 833 amino acids, respectively, and differing primarily in the lengths of their N- and C-terminal tails) have been described, STIM1 is the most interesting for the purposes of this chapter as it was found to act not only as a sensor within the stores [17, 18, 65] but also to play a role in the plasma membrane [17, 20] to activate I CRAC.
From a structural point of view, STIM1 is a Ca2+-binding protein (within either the ER lumen or extracellular space) that includes a number of functional domains described in Table 23.1. Both STIM1 and STIM2 can be phosphorylated predominantly on serine and threonine residues. In addition, STIM1 contains an additional N-linked glycosylation site within the SAM domain itself [66]. STIM1 has been reported to be expressed at the cell surface, as well as in the ER membrane, while STIM2 is expressed only intracellularly, likely reflecting an ER-retention signal (KKXX) present in STIM2 but not in STIM1 [67].
Knockdown of STIM1 by siRNA or functional knockdown of STIM1 by electrotransjection of neutralizing antibodies reduces SOCE in different cell types [20, 68] and I CRAC in Jurkat T cells [20]. Evidence supporting the role of STIM1 in SOCE reports that mutation of the Ca2+-binding EF-hand domain of STIM1 leads to constitutive SOC channel activation, and subsequent entry of Ca2+ into the cytoplasm, even without any detectable change in the content of the Ca2+ stores [17].
It is noteworthy to mention that, in addition to its role as an ER Ca2+ sensor, STIM1 has been found in the plasma membrane in a number of cells, expressing the EF-hand domain in the cell surface and acting as an extracellular Ca2+ sensor, where it has been demonstrated to modulate the operation of CRAC and SOC channels. External application of an antibody addressed towards the STIM1 N-terminal EF-hand region has been reported to block both CRAC channels in hematopoietic cells and SOC channels in HEK293 cells [20]. In addition, external application of the anti-STIM1 antibody blocks the inhibition of SOCE induced by increasing extracellular Ca2+ concentrations in human platelets, revealing a role for plasma membrane-resident STIM1 in the modulation of SOCE by extracellular Ca2+, probably through its interaction with Ca2+ channel subunits such as Orai1 [19]. The pool of STIM1 that resides in the plasma membrane has also been reported to play a key role in other mechanisms of Ca2+ entry different from SOCE, such as the store-independent, arachidonic acid-activated, ARC channels, which show high Ca2+-selectivity and low conductance and co-exist with CRAC channels [69].
In the 2006, Vig and co-workers demonstrated that the Ca2+ release-activated Ca2+ channel protein 1 (CRACM1) is a plasma membrane protein essential for SOCE. Although overexpression of the CRACM1 did not affect CRAC currents, RNAi-mediated knockdown disrupted its activation. Also, they reported that CRACM1 could be the CRAC channel itself, a subunit of it, or a component of the CRAC signalling machinery [22]. Few months later, the same group demonstrated that STIM1 and CRACM1 interact functionally; the overexpression of both proteins greatly potentiated I CRAC, suggesting that STIM1 and CRACM1 mutually limit store-operated currents and that CRACM1 may be the long-sought CRAC channel [70]. Today, CRACM1 is best known for the romantic name of Orai1 (in Greek mythology, the “Orai” are the keepers of the gates of heaven). The mammalian Orai family has two additional homologs, Orai2 and Orai3. Orai proteins share no homology with any other known ion channel family or cellular proteins.
Orai1, a Ca2+ selective ion channel, is a 301 amino acids protein with four transmembrane domains and a number of functional regions depicted in Table 23.2. Maruyama et al. [71] have purified Orai1 in its tetrameric form and have reconstructed the three-dimensional structure from electron microscopic images, providing the first depiction of an Orai family member. According to these authors, Orai1 is a teardrop-shaped molecule 150 Å in height, 95 Å in side length, and 105 Å diagonally at the widest transmembrane region.
The structure of Orai2 and Orai3 is similar to that of their homolog Orai 1 [72, 73]. All three Orai isoforms constitute Ca2+ selective plasma membrane channels, whose currents have been shown to be inhibited by extracellular Ca2+ [74]. The three Orai isoforms can be activated by store depletion when co-expressed with STIM1 although the amplitude of the currents generated are smaller for Orai2 and Orai3, which might reflect that they interact with STIM1 with less efficiency [75, 76]. Orai isoforms show slightly different selectivity for Na+ (being Orai3 more permeable for Na+) and distinct sensitivity to the pharmacological agent 2-aminoethoxydiphenyl borate (2-APB) [75]. While Orai1 currents are stimulated by low concentrations of 2-APB and abolished by high 2-APB concentrations, Orai2 currents are only partially sensitive to this inhibitor and Orai3 is stimulated by 2-APB [75, 77, 78].
23.4 STIM1-Orai1-TRPC Communication
The nature of the interaction between STIM1 and the plasma membrane Ca2+ channel subunits is currently under intense investigation by a number of research teams in order to determine the mechanism underlying the activation of capacitative channels by STIM1. In 2008, Romanin’s group demonstrated a dynamic interaction between STIM1 and Orai1 involving the C-termini of both proteins using Forster resonance energy transfer (FRET) microscopy. Interestingly, the Orai1 R91W mutant associated to SCID syndrome did not impair the interaction with STIM1 but altered the activation of Ca2+ currents [79]. The coiled-coil C-terminal domain of STIM1 has been reported to trigger dimerization of Orai dimers resulting in the formation of tetrameric Orai1 channels to activate I CRAC [80].
Four research groups have identified in parallel that a cytoplasmic STIM1 region composed of an ezrin-radixin-moesin domain is essential for the activation of Orai1. This region has been named SOAR (STIM1 Orai-activating region) [81], OASF (Orai-activating small fragment) [82], CAD (CRAC-activating domain) [83] and CCb9 [84]. The four regions, SOAR (including the STIM1 amino acid residues 344–442), OASF (amino acids 233–450/474), CAD (amino acids 342–448) and CCb9 (amino acids 339–444), are located within STIM1 C-terminus and comprise two coiled-coil domains and an amino acid sequence that enhances interaction with Orai1, resulting in increased Ca2+ currents. These studies have reported several features of the Orai1-STIM1 interacting region: OASF has been reported to be able to homomerize by a novel assembly domain that occurred subsequent to the coiled-coil domains. In addition, STIM1 oligomerization has been shown to be required for CAD exposure. Furthermore, the SOAR region is able to activate all known Orai isoforms although with different conductances being greater for Orai1 than for Orai2 or Orai3 [81, 82].
In addition, a regulatory domain at aminoacids 474–485 of the cytosolic STIM1 region, containing 7 negatively charged residues, known as CMD (CRAC modulatory domain)/CDI (Ca2+-dependent inactivation, reported as residues 470–491), has recently been described. This domain generates a signal that promotes Orai/CRAC channel closure in a Ca2+ concentration-dependent manner, a process known as fast, Ca2+-dependent inactivation of the Orai channels [85–87].
The interaction of STIM1 with Orai1, following depletion of the intracellular Ca2+ stores, results in a conformational change in Orai1, as determined by FRET, that might be important for CRAC channel activity [88]. FRET analysis between STIM1-YFP and Orai1-CFP has revealed that STIM1 and Orai1 approach within 100 Å or less after treatment with thapsigargin to induce store depletion. Simultaneously, the interaction Orai1-Orai1 is reversibly reduced upon depletion of the stores or application of extracellular Ca2+, both inducing CRAC channel activation, thus suggesting that Orai1 is subjected to a conformational rearrangement that is relevant, although not sufficient, for CRAC channel function [88].
In 2006, Huang and coworkers reported that STIM1 is able to gate TRPC1 [89]. The association of STIM1 with the TRPC proteins has been shown to be mediated by the STIM1 ERM domain [89]. More recently, the SOAR region, which has been shown to interact with Orai1 (see above), has been presented as the domain that binds to the TRPC channels [90]. The initial studies by Huang and coworkers reported that the STIM1 K-domain plays an important role in TRPC1 channel gating, although is not necessary for the interaction between STIM1 and TRPC1 [89]. Muallem’s team has recently reported that STIM1 gates TRPC1 through the interaction between two conserved, negatively charged, aspartates in TRPC1 ((639)DD(640)) with the positively charged lysine residues in STIM1((684)KK(685)) located in the C-terminal polybasic region. Different charge swapping experiments confirm that STIM1 gates TRPC1 by intermolecular electrostatic interaction [91]. A similar activation mechanism has been reported for TRPC3 mediated by the negatively charged 697 and 698 aspartate residues [91]. However, STIM1 operates Orai1 by a different mechanism since the C-terminal polybasic and serine-proline rich region of STIM1 are not required for activation of Orai1 [91]. Functional association between STIM1 and TRPC1 has been reported in a number of endogenously expressing and transfected cell types, including HEK-293 cells [89, 92–95], Jurkat T cells [89], human platelets [68], salivary gland cells [96], mesangial cells [97], mouse pulmonary arterial smooth muscle cells [98], the hepatic cell line HL-7702 cells [99] and human parathyroid cells [100]. It is noteworthy to mention that association of STIM1 with TRPC1 has not been found in HEK-293 cells co-transfected with both proteins, where STIM1 overexpression has not reported an increase in the activity of different TRPCs in these cells [101], and vascular smooth muscle cells [102]. The reason of this discrepancy, which might reside on the different transfection levels or the idiosyncrasy of the cell type, is still unclear and requires further studies to fully understand.
23.5 Calcium Entry Pathways Mediated by STIM1-Orai1-TRPC Complexes
The nature of the capacitative channels, as well as the mechanisms that gate them after Ca2+ stores have been depleted, have been a matter of intense investigation since the identification of SOCE. One of the earliest hypotheses was formulated in sea urchin eggs, where inositol 1,3,4,5-tetrakisphosphate (IP4) was suggested to modulate Ca2+ entry into the IP3-sensitive pool by physical interaction between IP3 and IP4 receptors located in the plasma membrane and the ER membrane, respectively [103, 104]. The role of IP3 receptors in SOCE has been widely investigated and a relationship between TRP proteins and IP3 receptors has been demonstrated in different cell types, including HEK 293 cells, where exogenously expressed TRPC3 can be activated by an IP3 receptor-dependent physical coupling mechanism [105], T3 cells stably expressing epitope-tagged TRPC3 or TRPC6, where IP3 receptor is detected in TRP immunoprecipitates [106], and human platelets, where endogenously expressed type II IP3 receptor has been found in TRPC1 immunoprecipitates only after depletion of the intracellular Ca2+ stores and independently of rises in [Ca2+]c, which indicates that this interaction is capacitative in nature [107–110]. IP3 receptors, such as the type I IP3 receptor, have also been reported to participate in agonist-induced, probably non-capacitative, Ca2+ entry by interaction with TRPC3, the scaffold protein RACK1 (receptor for activated C-kinase-1), STIM1 and Orai1 [111, 112]. However, although the IP3 receptors might play an important role in agonist-induced Ca2+ entry, they lack Ca2+ sensing capability.
With the identification of STIM1 as the ER Ca2+ sensor, studies concerning the communication between the ER and the plasma membrane channels focused on this protein. It is widely accepted that a functional protein-protein interaction between STIM1 and Orai1 results in the activation of SOCE. STIM1 enhances SOCE when co-expressed with Orai1 [70, 113, 114], as well as with Orai2 [113] and Orai3 [75, 78], which suggests that these combinations of proteins are sufficient to mediate the process of SOCE, although with distinct inactivation profiles and permeability properties. Special attention has been focused on the study of the interaction between STIM1 and Orai1. In HEK-293 cells, which show significant SOCE while the level of endogenous CRAC is extremely low, expression of Orai1 alone clearly reduced SOCE; however, when co-expressed with STIM1, Orai1 induces a dramatic gain in the amount of SOCE [114]. The inhibition of SOCE by Orai1 overexpression suggests that an adequate stoichiometrical relationship between STIM1 and Orai1 is necessary for this process [114]. Consistent with this, store depletion has been reported to lead to aggregation and translocation of STIM1 in close apposition to the plasma membrane in order to recruit Orai1 and assemble functional units of CRAC channels in a stoichiometric manner [115]. Studies based on electrophysiology, single-molecule fluorescence bleaching methods and FRET have demonstrated that the CRAC channels are formed by four Orai1 monomers assembled to form a tetrameric structure, which is associated to two STIM1 molecules [24, 80, 116] (Fig. 23.1). However, it remains unclear whether this is the only configuration that results in CRAC channel activation. In fact, studies in cells expressing Orai1 and STIM1 at different ratios (from 4:1 to 1:4) have reported that low Orai1:STIM1 ratios results in I CRAC with strong fast Ca2+-dependent inactivation, while high Orai1:STIM1 ratios produce I CRAC with strong activation at negative potentials. In addition, the Orai1:STIM1 expression ratio affects Ca2+, Ba2+ and Sr2+ conductance; thus suggesting that the biophysical properties of the channels formed by Orai1 depend on the stoichiometry of its interaction with STIM1 [117].
Soon after the identification of STIM1, Huang and coworkers reported that the cytosolic C-terminus of STIM1 is sufficient to activate TRPC1 channels and SOCE [89]. The association of STIM1 and TRPC1 has been reported in a number of cell types and models including human platelets endogenously expressing TRPC1 and STIM1 [68, 118, 119], rat basophilic leukemia cells [96] or HEK293 cells [120]. In addition, STIM1 has been reported to associate with other members of the TRPC family including TRPC2 [93], TRPC4, TRPC5 [92] and TRPC6 [63], although the interaction with TRPC6 has been challenged by Yuan and coworkers, suggesting that STIM1 regulates its function indirectly by promoting the heteromultimerization of TRPC6 with TRPC4 [92]. The direct or indirect association between STIM1 and TRPC6 observed in human platelets [63] and HEK293 cells [92] might be due to the idiosyncrasy of the cells or the different expression of the proteins investigated, endogenous in human platelets, although whether the interaction between TRPC6 and STIM1 is mediated by TRPC4, or other TRPC family members, has not been investigated in these cells yet.
Interestingly, the association of STIM1 to TRPC1 has been reported to recruit TRPC1 into lipid rafts, where TRPC1 functions as a SOC channel, while in the absence of STIM1, TRPC1 interacts with other TRPC family members resulting in the formation of receptor-operated Ca2+ (ROC) channels (Fig. 23.1); thus providing evidence for a role of STIM1 in the regulation of TRPC1 participation in SOCE or ROCE and highlighting the role of lipid rafts in the modulation of TRPC1 channel function [121]. Lipid rafts are plasma membrane domains that contain high concentrations of cholesterol and sphingolipids. Lipid rafts recruit certain signalling molecules while excluding others. For instance, in human platelets, only TRPC1, 4 and 5 were found to associate with plasma membrane lipid rafts, while TRPC3 or TRPC6 were not found in these domains [59]. A number of studies based on the use of methyl-β-cyclodextrin (MBCD), a compound that forms soluble complexes with cholesterol and thus deplete membrane cholesterol [122], have reported that lipid raft domains are essential for the assembly of signalling complexes, although it should be taken into account that cells might restore the cholesterol level in the plasma membrane by mobilising cholesterol from intracellular cholesterol stores [123]. Therefore, MBCD might reduce intracellular cholesterol levels, and sphingolipids also participate in lipid rafts and might maintain certain raft structure [124, 125]. Lipid rafts provide a favourable environment necessary for clustering of STIM1 at ER-plasma membrane junctions upon store depletion, facilitating the Ca2+ store-dependent interaction between STIM1 and TRPC1 and subsequent SOCE [126]. Lipid rafts have also been reported to play a crucial role in the association between STIM1 and the plasma membrane channel subunits TRPC1 and Orai1 after depletion of the intracellular Ca2+ stores and is also necessary for thapsigargin-induced Ca2+ entry in human platelets [119].
Recent studies have presented evidence for the existence of functional interactions between Orai1 and TRPCs under the influence of STIM1, and propose that SOC channels are composed of heteromeric complexes that include TRPCs and Orai proteins [25, 26, 96] (Fig. 23.1). Knockdown of Orai1 significantly reduces I SOC in human salivary gland cells [96], where TRPC1 has been demonstrated to be a major SOC channel subunit [127]. Consistent with this, Orai proteins have been reported to confer STIM1-mediated store depletion sensitivity to TRPC channels recruiting TRPC channels for the conduction of SOCE. In HEK293 cells overexpressing store-depletion insensitive TRPC3 or TRPC6, these TRPCs become sensitive to store depletion upon expression of exogenous Orai [26]. These observations suggest that the involvement of Orai proteins in SOCE might be well explained either by a model in which Orai1 are self-contained ion channels activated by STIM1, the proposed CRAC channel hypothesis [23, 70, 73, 128], or a model in which the SOC channels are formed by a combination of TRPCs and Orai proteins [26]. In the latter model, Orai proteins would communicate the information concerning the filling state of the intracellular Ca2+ stores from STIM, located in the ER, to TRPC proteins located in the plasma membrane. In support of a role for Orai conferring store-depletion sensitivity to TRPCs, these complexes have been found in non-transfected cells. In human platelets endogenously expressing STIM1, Orai1 and TRPC1, where electrotransjection with anti-STIM1 antibody, specific for the EF-hand domain, both prevented the interaction of STIM1 with hTRPC1 and reduced thapsigargin-evoked SOCE [68], a functional interaction between STIM1, Orai1 and TRPC1 in the activation of SOCE has been demonstrated [118]. In these cells, impairment of the interaction between STIM1 and Orai1, results in disruption of the association of STIM1 and TRPC1, and subsequently alters the behaviour of TRPC1 being no longer involved in SOCE but in ROCE mediated by DAG [118]. Similar results have been observed for TRPC6, in human platelets naturally expressing TRPC6 we have found that the participation of TRPC6 in SOCE or ROCE is regulated through its interaction with the Orai1-STIM1 complex or hTRPC3, respectively, in human platelets [63]; thus STIM1 located in the ER functions as a switch that communicates the filling state of the stores to SOC channels, involving TRPC proteins, through Orai1.
Interestingly, a number of reports have strongly suggested that Orai and TRPC proteins might form complexes that participate both in SOCE and ROCE. A study has reported that expression of Orai1, under experimental conditions that enhance SOCE, leads to the activation of ROCE. In addition, the R91W Orai1 mutant, responsible for SCID, has been shown to block both SOCE and DAG-activated ROCE into cells that, stably or transiently, express TRPC3 proteins [27]. To integrate these results with current data concerning Orai, TRPCs and STIM, it has been postulated that Orai-TRPC complexes recruited to lipid rafts mediate SOCE, whereas the same complexes mediate ROCE when they are outside of lipid rafts [27], which is consistent with previous studies reporting a role for lipid rafts in the modulation of TRPC function by STIM1 [121]. Therefore, there is a body of evidence supporting that TRPCs might be involved in the formation of ion channels responsible for ROCE or SOCE by receiving information from either PLC or STIM1-Orai, respectively [25–27, 63, 118, 120]. The activation of TRPCs by STIM1 has been challenged in a recent study, although, as reported by the authors, more complex combinations of STIM1, Orai1 and TRPCs, as described in Cheng et al. [120], Jardin et al. [63, 118] and Liao et al. [25–27] have not been addressed in that study [101]. Despite the current knowledge concerning Orai-TRPCs-STIM interactions, further studies are required to describe more accurately the molecular composition of the channels mediating SOCE and ROCE and to clarify whether the channel components are the same when Orai-TRPC complexes mediate ROCE or SOCE.
Abbreviations
- [Ca2+]c :
-
cytosolic free Ca2+ concentration
- ARC:
-
arachidonic acid-activated
- CAD:
-
CRAC-activating domain
- CMD:
-
CRAC modulatory domain
- CRAC:
-
Ca2+ release-activated Ca2+ channel
- DAG:
-
diacylglycerol
- ER:
-
endoplasmic reticulum
- FRET:
-
Forster resonance energy transfer
- IP3 :
-
inositol 3,4,5-trisphosphate
- IP4 :
-
inositol 1,3,4,5-tetrakisphosphate
- MBCD:
-
methyl-β-cyclodextrin
- OASF:
-
Orai-activating small fragment
- PIP2 :
-
phosphatidilinositol 4,5-bisphosphate
- PLC:
-
phospholipase C
- RACK1:
-
receptor for activated C-kinase-1
- ROCE:
-
receptor-operated Ca2+ entry
- SCID:
-
severe combined immune deficiency
- SERCA:
-
sarcoplasmic/endoplasmic-reticulum Ca2+-ATPase
- SOC:
-
store-operated channel
- SOAR:
-
STIM1 Orai-activating region
- SOCE:
-
store-operated calcium entry
- STIM1:
-
stromal interaction molecule 1
- TRP:
-
transient receptor potential
- TG:
-
thapsigargin.
References
Petersen OH (2002) Calcium signal compartmentalization. Biol Res 35:177–182
Putney JW Jr (1986) A model for receptor-regulated calcium entry. Cell Calcium 7:1–12
Wedel B, Boyles RR, Putney JW Jr, Bird GS (2007) Role of the store-operated calcium entry proteins Stim1 and Orai1 in muscarinic cholinergic receptor-stimulated calcium oscillations in human embryonic kidney cells. J Physiol 579:679–689
Berridge MJ (1995) Capacitative calcium entry. Biochem J 312(Pt 1):1–11
Redondo PC, Harper MT, Rosado JA, Sage SO (2006) A role for cofilin in the activation of store-operated calcium entry by de novo conformational coupling in human platelets. Blood 107:973–979
Verkhratsky A (2005) Physiology and pathophysiology of the calcium store in the endoplasmic reticulum of neurons. Physiol Rev 85:201–279
Hoth M, Penner R (1992) Depletion of intracellular calcium stores activates a calcium current in mast cells. Nature 355:353–356
Bakowski D, Parekh AB (2000) Voltage-dependent conductance changes in the store-operated Ca2+ current ICRAC in rat basophilic leukaemia cells. J Physiol 529(Pt 2):295–306
Luik RM, Wang B, Prakriya M, Wu MM, Lewis RS (2008) Oligomerization of STIM1 couples ER calcium depletion to CRAC channel activation. Nature 454:538–542
Parekh AB, Penner R (1997) Store depletion and calcium influx. Physiol Rev 77:901–930
Zweifach A, Lewis RS (1993) Mitogen-regulated Ca2+ current of T lymphocytes is activated by depletion of intracellular Ca2+ stores. Proc Natl Acad Sci U S A 90:6295–6299
Parekh AB, Putney JW Jr (2005) Store-operated calcium channels. Physiol Rev 85:757–810
Trepakova ES, Gericke M, Hirakawa Y, Weisbrod RM, Cohen RA, Bolotina VM (2001) Properties of a native cation channel activated by Ca2+ store depletion in vascular smooth muscle cells. J Biol Chem 276:7782–7790
Smani T, Zakharov SI, Csutora P, Leno E, Trepakova ES, Bolotina VM (2004) A novel mechanism for the store-operated calcium influx pathway. Nat Cell Biol 6:113–120
Albert AP, Saleh SN, Peppiatt-Wildman CM, Large WA (2007) Multiple activation mechanisms of store-operated TRPC channels in smooth muscle cells. J Physiol 583:25–36
Guibert C, Ducret T, Savineau JP (2008) Voltage-independent calcium influx in smooth muscle. Prog Biophys Mol Biol 98:10–23
Zhang SL, Yu Y, Roos J, Kozak JA, Deerinck TJ, Ellisman MH, Stauderman KA, Cahalan MD (2005) STIM1 is a Ca2+ sensor that activates CRAC channels and migrates from the Ca2+ store to the plasma membrane. Nature 437:902–905
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
Jardin I, Lopez JJ, Redondo PC, Salido GM, Rosado JA (2009) Store-operated Ca2+ entry is sensitive to the extracellular Ca2+ concentration through plasma membrane STIM1. Biochim Biophys Acta 1793:1614–1622
Spassova MA, Soboloff J, He LP, Xu W, Dziadek MA, Gill DL (2006) STIM1 has a plasma membrane role in the activation of store-operated Ca(2+) channels. Proc Natl Acad Sci U S A 103:4040–4045
Feske S, Gwack Y, Prakriya M, Srikanth S, Puppel SH, Tanasa B, Hogan PG, Lewis RS, Daly M, Rao A (2006) A mutation in Orai1 causes immune deficiency by abrogating CRAC channel function. Nature 441:179–185
Vig M, Peinelt C, Beck A, Koomoa DL, Rabah D, Koblan-Huberson M, Kraft S, Turner H, Fleig A, Penner R, Kinet JP (2006) CRACM1 is a plasma membrane protein essential for store-operated Ca2+ entry. Science 312:1220–1223
Yeromin AV, Zhang SL, Jiang W, Yu Y, Safrina O, Cahalan MD (2006) Molecular identification of the CRAC channel by altered ion selectivity in a mutant of Orai. Nature 443:226–229
Mignen O, Thompson JL, Shuttleworth TJ (2008) Orai1 subunit stoichiometry of the mammalian CRAC channel pore. J Physiol 586:419–425
Liao Y, Erxleben C, Abramowitz J, Flockerzi V, Zhu MX, Armstrong DL, Birnbaumer L (2008) Functional interactions among Orai1, TRPCs, and STIM1 suggest a STIM-regulated heteromeric Orai/TRPC model for SOCE/Icrac channels. Proc Natl Acad Sci U S A 105:2895–2900
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
Liao Y, Plummer NW, George MD, Abramowitz J, Zhu MX, Birnbaumer L (2009) A role for Orai in TRPC-mediated Ca2+ entry suggests that a TRPC:Orai complex may mediate store and receptor operated Ca2+ entry. Proc Natl Acad Sci U S A 106:3202–3206
Salido GM, Sage SO, Rosado JA (2009) TRPC channels and store-operated Ca(2+) entry. Biochim Biophys Acta 1793:223–230
Salido GM, Sage SO, Rosado JA (2009) Biochemical and functional properties of the store-operated Ca2+ channels. Cell Signal 21:457–461
Liu X, Cheng KT, Bandyopadhyay BC, Pani B, Dietrich A, Paria BC, Swaim WD, Beech D, Yildrim E, Singh BB, Birnbaumer L, Ambudkar IS (2007) Attenuation of store-operated Ca2+ current impairs salivary gland fluid secretion in TRPC1(-/-) mice. Proc Natl Acad Sci U S A 104:17542–17547
Cahalan MD (2009) STIMulating store-operated Ca(2+) entry. Nat Cell Biol 11:669–677
Liu X, Wang W, Singh BB, Lockwich T, Jadlowiec J, O’Connell B, Wellner R, Zhu MX, Ambudkar IS (2000) Trp1, a candidate protein for the store-operated Ca(2+) influx mechanism in salivary gland cells. J Biol Chem 275:3403–3411
Brough GH, Wu S, Cioffi D, Moore TM, Li M, Dean N, Stevens T (2001) Contribution of endogenously expressed Trp1 to a Ca2+-selective, store-operated Ca2+ entry pathway. FASEB J 15:1727–1738
Rosado JA, Brownlow SL, Sage SO (2002) Endogenously expressed Trp1 is involved in store-mediated Ca2+ entry by conformational coupling in human platelets. J Biol Chem 277:42157–42163
Xu SZ, Beech DJ (2001) TrpC1 is a membrane-spanning subunit of store-operated Ca(2+) channels in native vascular smooth muscle cells. Circ Res 88:84–87
Louis M, Zanou N, Van Schoor M, Gailly P (2008) TRPC1 regulates skeletal myoblast migration and differentiation. J Cell Sci 121:3951–3959
Hardie RC, Minke B (1992) The trp gene is essential for a light-activated Ca2+ channel in Drosophila photoreceptors. Neuron 8:643–651
Phillips AM, Bull A, Kelly LE (1992) Identification of a Drosophila gene encoding a calmodulin-binding protein with homology to the trp phototransduction gene. Neuron 8:631–642
Hardie RC, Reuss H, Lansdell SJ, Millar NS (1997) Functional equivalence of native light-sensitive channels in the Drosophila trp301 mutant and TRPL cation channels expressed in a stably transfected Drosophila cell line. Cell Calcium 21:431–440
Hardie RC (2003) Regulation of TRP channels via lipid second messengers. Annu Rev Physiol 65:735–759
Wes PD, Chevesich J, Jeromin A, Rosenberg C, Stetten G, Montell C (1995) TRPC1, a human homolog of a Drosophila store-operated channel. Proc Natl Acad Sci U S A 92: 9652–9656
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
Petersen CC, Berridge MJ, Borgese MF, Bennett DL (1995) Putative capacitative calcium entry channels: expression of Drosophila trp and evidence for the existence of vertebrate homologues. Biochem J 311(Pt 1):41–44
Montell C, Birnbaumer L, Flockerzi V, Bindels RJ, Bruford EA, Caterina MJ, Clapham DE, Harteneck C, Heller S, Julius D, Kojima I, Mori Y, Penner R, Prawitt D, Scharenberg AM, Schultz G, Shimizu N, Zhu MX (2002) A unified nomenclature for the superfamily of TRP cation channels. Mol Cell 9:229–231
Pedersen SF, Owsianik G, Nilius B (2005) TRP channels: an overview. Cell Calcium 38:233–252
Hoenderop JG, Voets T, Hoefs S, Weidema F, Prenen J, Nilius B, Bindels RJ (2003) Homo- and heterotetrameric architecture of the epithelial Ca2+ channels TRPV5 and TRPV6. EMBO J 22:776–785
Vannier B, Zhu X, Brown D, Birnbaumer L (1998) The membrane topology of human transient receptor potential 3 as inferred from glycosylation-scanning mutagenesis and epitope immunocytochemistry. J Biol Chem 273:8675–8679
Vazquez G, Wedel BJ, Aziz O, Trebak M, Putney JW Jr (2004) The mammalian TRPC cation channels. Biochim Biophys Acta 1742:21–36
Montell C, Birnbaumer L, Flockerzi V (2002) The TRP channels, a remarkably functional family. Cell 108:595–598
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
Birnbaumer L, Zhu X, Jiang M, Boulay G, Peyton M, Vannier B, Brown D, Platano D, Sadeghi H, Stefani E, Birnbaumer M (1996) On the molecular basis and regulation of cellular capacitative calcium entry: roles for Trp proteins. Proc Natl Acad Sci U S A 93: 15195–15202
Thebault S, Zholos A, Enfissi A, Slomianny C, Dewailly E, Roudbaraki M, Parys J, Prevarskaya N (2005) Receptor-operated Ca2+ entry mediated by TRPC3/TRPC6 proteins in rat prostate smooth muscle (PS1) cell line. J Cell Physiol 204:320–328
Ben-Amor N, Redondo PC, Bartegi A, Pariente JA, Salido GM, Rosado JA (2006) A role for 5,6-epoxyeicosatrienoic acid in calcium entry by de novo conformational coupling in human platelets. J Physiol 570:309–323
Brownlow SL, Harper AG, Harper MT, Sage SO (2004) A role for hTRPC1 and lipid raft domains in store-mediated calcium entry in human platelets. Cell Calcium 35:107–113
Vannier B, Peyton M, Boulay G, Brown D, Qin N, Jiang M, 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 96: 2060–2064
Vazquez G, Wedel BJ, Trebak M, St John Bird G, Putney JW Jr (2003) Expression level of the canonical transient receptor potential 3 (TRPC3) channel determines its mechanism of activation. J Biol Chem 278: 21649–21654
Yildirim E, Kawasaki BT, Birnbaumer L (2005) Molecular cloning of TRPC3a, an N-terminally extended, store-operated variant of the human C3 transient receptor potential channel. Proc Natl Acad Sci U S A 102:3307–3311
Philipp S, Cavalie A, Freichel M, Wissenbach U, Zimmer S, Trost C, Marquart A, Murakami M, Flockerzi V (1996) A mammalian capacitative calcium entry channel homologous to Drosophila TRP and TRPL. EMBO J 15:6166–6171
Brownlow SL, Sage SO (2005) Transient receptor potential protein subunit assembly and membrane distribution in human platelets. Thromb Haemost 94:839–845
Philipp S, Hambrecht J, Braslavski L, Schroth G, Freichel M, Murakami M, Cavalie A, Flockerzi V (1998) A novel capacitative calcium entry channel expressed in excitable cells. EMBO J 17:4274–4282
Jardin I, Redondo PC, Salido GM, Rosado JA (2008) Phosphatidylinositol 4,5-bisphosphate enhances store-operated calcium entry through hTRPC6 channel in human platelets. Biochim Biophys Acta 1783:84–97
Brechard S, Melchior C, Plancon S, Schenten V, Tschirhart EJ (2008) Store-operated Ca(2+) channels formed by TRPC1, TRPC6 and Orai1 and non-store-operated channels formed by TRPC3 are involved in the regulation of NADPH oxidase in HL-60 granulocytes. Cell Calcium 44:492–506
Jardin I, Gomez LJ, Salido GM, Rosado JA (2009) Dynamic interaction of hTRPC6 with the Orai1-STIM1 complex or hTRPC3 mediates its role in capacitative or non-capacitative Ca(2+) entry pathways. Biochem J 420:267–276
Lievremont JP, Bird GS, Putney JW Jr (2004) Canonical transient receptor potential TRPC7 can function as both a receptor- and store-operated channel in HEK-293 cells. Am J Physiol Cell Physiol 287:C1709–C1716
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
Williams RT, Manji SS, Parker NJ, Hancock MS, Van Stekelenburg L, Eid JP, Senior PV, Kazenwadel JS, Shandala T, Saint R, Smith PJ, Dziadek MA (2001) Identification and characterization of the STIM (stromal interaction molecule) gene family: coding for a novel class of transmembrane proteins. Biochem J 357:673–685
Soboloff J, Spassova MA, Hewavitharana T, He LP, Xu W, Johnstone LS, Dziadek MA, Gill DL (2006) STIM2 is an inhibitor of STIM1-mediated store-operated Ca2+ Entry. Curr Biol 16:1465–1470
Lopez JJ, Salido GM, Pariente JA, Rosado JA (2006) Interaction of STIM1 with endogenously expressed human canonical TRP1 upon depletion of intracellular Ca2+ stores. J Biol Chem 281:28254–28264
Mignen O, Thompson JL, Shuttleworth TJ (2009) The molecular architecture of the arachidonate-regulated Ca2+-selective ARC channel is a pentameric assembly of Orai1 and Orai3 subunits. J Physiol 587:4181–4197
Peinelt C, Vig M, Koomoa DL, Beck A, Nadler MJ, Koblan-Huberson M, Lis A, Fleig A, Penner R, Kinet JP (2006) Amplification of CRAC current by STIM1 and CRACM1 (Orai1). Nat Cell Biol 8:771–773
Maruyama Y, Ogura T, Mio K, Kato K, Kaneko T, Kiyonaka S, Mori Y, Sato C (2009) Tetrameric Orai1 Is a Teardrop-shaped Molecule with a Long, Tapered Cytoplasmic Domain. J Biol Chem 284:13676–13685
Cahalan MD, Zhang SL, Yeromin AV, Ohlsen K, Roos J, Stauderman KA (2007) Molecular basis of the CRAC channel. Cell Calcium 42:133–144
Prakriya M, Feske S, Gwack Y, Srikanth S, Rao A, Hogan PG (2006) Orai1 is an essential pore subunit of the CRAC channel. Nature 443:230–233
DeHaven WI, Smyth JT, Boyles RR, Putney JW Jr (2007) Calcium inhibition and calcium potentiation of Orai1, Orai2, and Orai3 calcium release-activated calcium channels. J Biol Chem 282:17548–17556
Lis A, Peinelt C, Beck A, Parvez S, Monteilh-Zoller M, Fleig A, Penner R (2007) CRACM1, CRACM2, and CRACM3 are store-operated Ca2+ channels with distinct functional properties. Curr Biol 17:794–800
Frischauf I, Schindl R, Derler I, Bergsmann J, Fahrner M, Romanin C (2008) The STIM/Orai coupling machinery. Channels (Austin) 2:261–268
Peinelt C, Lis A, Beck A, Fleig A, Penner R (2008) 2-Aminoethoxydiphenyl borate directly facilitates and indirectly inhibits STIM1-dependent gating of CRAC channels. J Physiol 586:3061–3073
Schindl R, Bergsmann J, Frischauf I, Derler I, Fahrner M, Muik M, Fritsch R, Groschner K, Romanin C (2008) 2-aminoethoxydiphenyl borate alters selectivity of Orai3 channels by increasing their pore size. J Biol Chem 283:20261–20267
Muik M, Frischauf I, Derler I, Fahrner M, Bergsmann J, Eder P, Schindl R, Hesch C, Polzinger B, Fritsch R, Kahr H, Madl J, Gruber H, Groschner K, Romanin C (2008) Dynamic coupling of the putative coiled-coil domain of ORAI1 with STIM1 mediates ORAI1 channel activation. J Biol Chem 283:8014–8022
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
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
Muik M, Fahrner M, Derler I, Schindl R, Bergsmann J, Frischauf I, Groschner K, Romanin C (2009) A Cytosolic Homomerization and a Modulatory Domain within STIM1 C Terminus Determine Coupling to ORAI1 Channels. J Biol Chem 284:8421–8426
Park CY, Hoover PJ, Mullins FM, Bachhawat P, Covington ED, Raunser S, Walz T, Garcia KC, Dolmetsch RE, Lewis RS (2009) STIM1 clusters and activates CRAC channels via direct binding of a cytosolic domain to Orai1. Cell 136:876–890
Kawasaki T, Lange I, Feske S (2009) A minimal regulatory domain in the C terminus of STIM1 binds to and activates ORAI1 CRAC channels. Biochem Biophys Res Commun 385:49–54
Derler I, Fahrner M, Muik M, Lackner B, Schindl R, Groschner K, Romanin C (2009) A CRAC modulatory domain (CMD) within STIM1 mediates fast Ca2+-dependent inactivation of ORAI1 channels. J Biol Chem 284:24933–24938
Lee KP, Yuan JP, Zeng W, So I, Worley PF, Muallem S (2009) Molecular determinants of fast Ca2+-dependent inactivation and gating of the Orai channels. Proc Natl Acad Sci U S A 106:14687–14692
Mullins FM, Park CY, Dolmetsch RE, Lewis RS (2009) STIM1 and calmodulin interact with Orai1 to induce Ca2+-dependent inactivation of CRAC channels. Proc Natl Acad Sci U S A 106:15495–15500
Navarro-Borelly L, Somasundaram A, Yamashita M, Ren D, Miller RJ, Prakriya M (2008) STIM1-Orai1 interactions and Orai1 conformational changes revealed by live-cell FRET microscopy. J Physiol 586:5383–5401
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
Lee KP, Yuan JP, Hong JH, So I, Worley PF, Muallem S (2009) An endoplasmic reticulum/plasma membrane junction: STIM1/Orai1/TRPCs. FEBS Lett 584:2022–2027
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
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
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
Sampieri A, Zepeda A, Saldaña C, Salgado A, Vaca L (2008) STIM1 converts TRPC1 from a receptor-operated to a store-operated channel: Moving TRPC1 in and out of lipid rafts. Cell Calcium 44:479–491
Kim MS, Zeng W, Yuan JP, Shin DM, Worley PF, Muallem S (2009) Native Store-operated Ca2+ Influx Requires the Channel Function of Orai1 and TRPC1. J Biol Chem 284:9733–9741
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
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 (Maywood) 234:673–682
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
Zhang ZY, Pan LJ, Zhang ZM (2009) Functional interactions among STIM1, Orai1 and TRPC1 on the activation of SOCs in HL-7702 cells. Amino Acids 39:195–204
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
DeHaven WI, Jones BF, Petranka JG, Smyth JT, Tomita T, Bird GS, Putney JW Jr (2009) TRPC channels function independently of STIM1 and Orai1. J Physiol 587:2275–2298
Dietrich A, Kalwa H, Storch U, Mederos y Schnitzler M, Salanova B, Pinkenburg O, Dubrovska G, Essin K, Gollasch M, Birnbaumer L, Gudermann T (2007) Pressure-induced and store-operated cation influx in vascular smooth muscle cells is independent of TRPC1. Pflugers Arch 455:465–477
Irvine RF, Moor RM (1987) Inositol(1,3,4,5)tetrakisphosphate-induced activation of sea urchin eggs requires the presence of inositol trisphosphate. Biochem Biophys Res Commun 146:284–290
Irvine RF (1992) Inositol phosphates and Ca2+ entry: toward a proliferation or a simplification? FASEB J 6:3085–3091
Kiselyov K, Xu X, Mozhayeva G, Kuo T, Pessah I, Mignery G, Zhu X, Birnbaumer L, Muallem S (1998) Functional interaction between InsP3 receptors and store-operated Htrp3 channels. Nature 396:478–482
Boulay G, Brown DM, Qin N, Jiang M, Dietrich A, Zhu MX, Chen Z, Birnbaumer M, Mikoshiba K, Birnbaumer L (1999) Modulation of Ca(2+) entry by polypeptides of the inositol 1,4, 5-trisphosphate receptor (IP3R) that bind transient receptor potential (TRP): evidence for roles of TRP and IP3R in store depletion-activated Ca(2+) entry. Proc Natl Acad Sci U S A 96:14955–14960
Rosado JA, Sage SO (2000) Coupling between inositol 1,4,5-trisphosphate receptors and human transient receptor potential channel 1 when intracellular Ca2+ stores are depleted. Biochem J 350(Pt 3):631–635
Rosado JA, Sage SO (2001) Activation of store-mediated calcium entry by secretion-like coupling between the inositol 1,4,5-trisphosphate receptor type II and human transient receptor potential (hTrp1) channels in human platelets. Biochem J 356:191–198
Rosado JA, Sage SO (2002) The ERK cascade, a new pathway involved in the activation of store-mediated calcium entry in human platelets. Trends Cardiovasc Med 12:229–234
Jardin I, Lopez JJ, Salido GM, Rosado JA (2008) Functional relevance of the de novo coupling between hTRPC1 and type II IP3 receptor in store-operated Ca2+ entry in human platelets. Cell Signal 20:737–747
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
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
Mercer JC, Dehaven WI, Smyth JT, Wedel B, Boyles RR, Bird GS, Putney JW Jr (2006) Large store-operated calcium selective currents due to co-expression of Orai1 or Orai2 with the intracellular calcium sensor, Stim1. J Biol Chem 281:24979–24990
Soboloff J, Spassova MA, Tang XD, Hewavitharana T, Xu W, Gill DL (2006) Orai1 and STIM reconstitute store-operated calcium channel function. J Biol Chem 281:20661–20665
Xu P, Lu J, Li Z, Yu X, Chen L, Xu T (2006) Aggregation of STIM1 underneath the plasma membrane induces clustering of Orai1. Biochem Biophys Res Commun 350:969–976
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
Scrimgeour N, Litjens T, Ma L, Barritt GJ, Rychkov GY (2009) Properties of Orai1 mediated store-operated current depend on the expression levels of STIM1 and Orai1 proteins. J Physiol 587:2903–2918
Jardin I, Lopez JJ, Salido GM, Rosado JA (2008) Orai1 mediates the interaction between STIM1 and hTRPC1 and regulates the mode of activation of hTRPC1-forming Ca2+ channels. J Biol Chem 283:25296–25304
Jardin I, Salido GM, Rosado JA (2008) Role of lipid rafts in the interaction between hTRPC1, Orai1 and STIM1. Channels (Austin) 2:401–403
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
Sampieri A, Angelica Z, Carlos S, Alfonso S, Vaca L (2008) STIM1 converts TRPC1 from a receptor-operated to a store-operated channel: moving TRPC1 in and out of lipid rafts. Cell Calcium 44:479–491
Klein U, Gimpl G, Fahrenholz F (1995) Alteration of the myometrial plasma membrane cholesterol content with beta-cyclodextrin modulates the binding affinity of the oxytocin receptor. Biochemistry 34:13784–13793
Mahammad S, Parmryd I (2007) Methyl-beta-cyclodextrin does not preferentially target lipid raft cholesterol. Chem Phys Lipids 149:85
Aubert-Jousset E, Garmy N, Sbarra V, Fantini J, Sadoulet MO, Lombardo D (2004) The combinatorial extension method reveals a sphingolipid binding domain on pancreatic bile salt-dependent lipase: role in secretion. Structure 12:1437–1447
Vaca L SOCIC: The store-operated calcium influx complex. Cell Calcium doi:10.1016/j.ceca.2010.01.002
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
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
Lorin-Nebel C, Xing J, Yan X, Strange K (2007) CRAC channel activity in C. elegans is mediated by Orai1 and STIM1 homologues and is essential for ovulation and fertility. J Physiol 580: 67–85
Zheng L, Stathopulos PB, Li GY, Ikura M (2008) Biophysical characterization of the EF-hand and SAM domain containing Ca2+ sensory region of STIM1 and STIM2. Biochem Biophys Res Commun 369:240–246
Fahrner M, Muik M, Derler I, Schindl R, Fritsch R, Frischauf I, Romanin C (2009) Mechanistic view on domains mediating STIM1-Orai coupling. Immunol Rev 231:99–112
Schindl R, Muik M, Fahrner M, Derler I, Fritsch R, Bergsmann J, Romanin C (2009) Recent progress on STIM1 domains controlling Orai activation. Cell Calcium 46:227–232
Soboloff J, Spassova MA, Dziadek MA, Gill DL (2006) Calcium signals mediated by STIM and Orai proteins–a new paradigm in inter-organelle communication. Biochim Biophys Acta 1763:1161–1168
Williams RT, Senior PV, Van Stekelenburg L, Layton JE, Smith PJ, Dziadek MA (2002) Stromal interaction molecule 1 (STIM1), a transmembrane protein with growth suppressor activity, contains an extracellular SAM domain modified by N-linked glycosylation. Biochim Biophys Acta 1596:131–137
Feske S (2009) ORAI1 and STIM1 deficiency in human and mice: roles of store-operated Ca2+ entry in the immune system and beyond. Immunol Rev 231:189–209
Liou J, Fivaz M, Inoue T, Meyer T (2007) Live-cell imaging reveals sequential oligomerization and local plasma membrane targeting of stromal interaction molecule 1 after Ca2+ store depletion. Proc Natl Acad Sci U S A 104:9301–9306
Takahashi Y, Murakami M, Watanabe H, Hasegawa H, Ohba T, Munehisa Y, Nobori K, Ono K, Iijima T, Ito H (2007) Essential role of the N-terminus of murine Orai1 in store-operated Ca2+ entry. Biochem Biophys Res Commun 356:45–52
Acknowledgments
This work was supported by M.E.C. grants BFU2007-60104 and BFU2010-21043-C02-01.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2011 Springer Science+Business Media B.V.
About this chapter
Cite this chapter
Salido, G.M., Jardín, I., Rosado, J.A. (2011). The TRPC Ion Channels: Association with Orai1 and STIM1 Proteins and Participation in Capacitative and Non-capacitative Calcium Entry. In: Islam, M. (eds) Transient Receptor Potential Channels. Advances in Experimental Medicine and Biology, vol 704. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-0265-3_23
Download citation
DOI: https://doi.org/10.1007/978-94-007-0265-3_23
Published:
Publisher Name: Springer, Dordrecht
Print ISBN: 978-94-007-0264-6
Online ISBN: 978-94-007-0265-3
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)