Store-Operated Channels: Diversity and Activation Mechanisms

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Science's STKE  27 Jul 2004:
Vol. 2004, Issue 243, pp. pe34
DOI: 10.1126/stke.2432004pe34


This perspective addresses two questions: How many store-operated channels (SOCs) are there, and how many mechanisms can account for SOC activation by depleted stores? Accumulating evidence suggests that the SOC family is not limited to the calcium-selective SOC that is responsible for ICRAC (Ca2+-SOC), but includes poorly selective cation SOCs (cat-SOCs) that may satisfy physiological needs in diverse excitable and nonexcitable cells. A growing number of studies in different cell types support the idea that all the members of SOC family (Ca2+-SOC and cat-SOC) may be activated by depletion of the stores through the same mechanism, which is mediated by calcium influx factor (CIF) and calcium-independent phospholipase A2 (iPLA2). A conformational coupling model is also discussed. To account for the most recent findings, we propose that two distinct classes of calcium-conducting channels may exist in plasma membrane, which respond to different signals: SOCs, which are activated by depletion of calcium stores through the CIF-iPLA2 mechanism [no inositol triphosphate (IP3) needed]; and IP3 receptor–operated channels (IP3ROCs), which are activated by IP3 receptor through a direct coupling mechanism (no store depletion is needed). This model, with two separate mechanisms linked to different channels, may resolve many conflicting findings and interpretations and may give a new perspective on the diversity of calcium influx pathways.

Activation of specific Ca2+-conducting channels in the plasma membrane is triggered by depletion of intracellular Ca2+ stores in diverse cell types, but the molecular identity of these store-operated channels (SOCs) and the mechanism of their activation remain the most intriguing and long-lasting mysteries in Ca2+ signaling (13).

Consensus on many issues related to the store-operated Ca2+ influx pathway has not yet been achieved, and debate continues regarding how many SOCs there are, and how many mechanisms may accommodate their activation by depleted stores.

First, how many SOCs may satisfy the physiological needs of different types of cells? In nonexcitable cells, a highly calcium-selective current (ICRAC) was found (4) and described in detail [for a review, see (57)]. This SOC remains a golden standard, and ICRAC is rightfully considered to be the best-defined whole-cell current that is activated by depletion of Ca2+ stores. Does this mean that all SOCs in different cells should have exactly the same ICRAC-like biophysical characteristics? Growing evidence suggests that calcium-selective SOC, which we call Ca2+-SOC and which generates ICRAC, is not the only SOC family member. Indeed, when standard procedures were used by different investigators to deplete the stores in various cells [by inhibition of sarcoplasmic and endoplasmic reticulum Ca-ATPase (SERCA), or cell dialysis with the calcium chelator BAPTA], instead of ICRAC, they recorded an inward cation current that developed with a similar time course and was sensitive to the same inhibitors, but showed different Ca2+ selectivity (823). Although not all of the studies provided rigorous biophysical characterization of these currents, it is clear that they are activated under the same experimental conditions as Ca2+-SOC is, but their relative Ca2+ to Na+ selectivity (pCa2+/pNa+) varies in different cell types from 40 to 1 (reflecting their ability to allow not only Ca2+, but also Na+ into the cell under physiological conditions). To distinguish them from Ca2+-SOC, we call these store-operated poorly selective cation channels "cat-SOC." Importantly, some investigators (using the same experimental conditions) were able to record Ca2+-SOC in one type of cells, and cat-SOC in another. For example, we have recorded Ca2+-SOC (with pCa2+/pNa+ ~ 1000) in rat basophilic leukemia (RBL) cells (24), and cat-SOC (with pCa2+/pNa+ = 1) in smooth muscle cells (SMCs) (11), whereas Ambudkar (25) compared Ca2+-SOC in RBL cells with cat-SOC in human submandibular gland cells (pCa2+/pNa+ = 40) and human parotid gland cells (pCa2+/pNa+ = 4). Thus, accumulating evidence suggests that the SOC family is not limited to Ca2+-SOC, but may have other cat-SOC members that are responsible for store-operated Ca2+ influx in diverse excitable and nonexcitable cells. Hopefully, the molecular architecture and subunit composition of different SOCs will be revealed soon.

Why may cells need SOCs with different relative selectivity to Ca2+ and Na+? In excitable cells, for example, activation of a poorly selective cation current may not only be the path for Ca2+ to enter the cell and refill the stores, but also may provide a depolarizing trigger to produce a secondary activation of voltage-gated Ca2+ channels (26), which may amplify Ca2+ influx required for different kinds of physiological responses in these cells. Another possible scenario is that Na+ influx through cat-SOCs, accompanied by membrane depolarization, can trigger secondary Ca2+ influx through the Na+/Ca2+ exchanger (working in a reverse mode) (2729). These are only a few of the advantages of poorly selective cat-SOC, instead of highly selective Ca2+-SOC, responding to store depletion.

The second question of continuing debate is: How many mechanisms are needed to trigger activation of different SOCs (Ca2+-SOC and cat-SOCs) in response to depletion of the stores? We believe that one mechanism may fit them all.

We found a new plasma membrane–delimited cascade of reactions, and proposed a novel mechanism for the store-operated Ca2+ influx pathway (30, 24), which is triggered by calcium influx factor (CIF, produced upon depletion of Ca2+ stores), involves Ca2+-independent phospholipase A2 (iPLA2) and its lysophospholipid products, and results in activation of SOC channels. The existence of CIF that is produced by depleted stores and the idea that it may trigger activation of store-operated channels was proposed more than a decade ago (31, 32). After initial excitement (33), the CIF model was strongly criticized because of a continuous uncertainty about the molecular identity and mechanism of action of CIF (2, 34, 35), but a few groups of CIF enthusiasts continued their struggle, attempting to identify native CIF and determine the CIF-mediated pathway (3642).

Finally, we proposed a simple model that may explain how CIF activates SOC channels (30, 24). First, we demonstrated that CIF activates cat-SOC channels (11) in excised membrane patches (43). Next, CIF-induced displacement of inhibitory calmodulin (CaM) from iPLA2 was found to be a key event leading to iPLA2 activation and generation of lysophospholipids, which in turn activate SOC channels in a plasma membrane–delimited fashion (Fig. 1). Upon refilling of the stores and termination of CIF production, CaM rebinds to iPLA2, inhibiting it, and the activity of SOC and Ca2+ influx is terminated. A physiological example of this process "in action" is agonist-induced activation and nitric oxide–induced inhibition of store-operated Ca2+ influx in vascular SMCs and human platelets (44, 45). It was no surprise that agonist-induced depletion of the stores activated capacitative Ca2+ influx and caused contraction in SMCs, but it was a surprise that nitric oxide may induce vascular relaxation by accelerating SERCA-dependent refilling of the stores, which shuts down CIF production and terminates the activity of SOC and Ca2+ influx.

Fig. 1.

Scheme illustrating the functional regulation of three distinct types of Ca2+ influx channels: IP3 receptor–operated channel (IP3ROC), store-operated channel (SOC), and voltage-gated Ca2+ channel (VGCC). Agonist binding to receptor (R) leads to G protein (G)–dependent activation of phospholipase C (PLC), production of IP3, and activation of IP3R in different compartments of endoplasmic reticulum. At subthreshold level, IP3 may bind to some IP3R and, through conformational coupling mechanism, activate distinct IP3ROC (which does not require Ca2+ release from the stores). Another type of channel, SOCs are activated specifically by depletion of endoplasmic reticulum Ca2+ stores as a result of IP3-induced Ca2+ release, or inhibition of SERCA-induced Ca2+ refilling. Upon store depletion, calcium influx factor (CIF, red dots) is produced by the stores and displaces inhibitory calmodulin (CaM) from Ca2+-independent phospholipase A2 (iPLA2), leading to activation of iPLA2 and production of lysophospholipids (LysoPL) that activate the SOC. Depending on calcium selectivity, under physiological conditions SOCs provide either only Ca2+ influx (through Ca2+-SOC) to refill the stores, or both Ca2+ and Na+ influx (through cat-SOC), which may also depolarize the plasma membrane and activate VGCCs, amplifying Ca2+ influx that may be used for physiological responses in functionally different compartments.

The mechanism of CIF-induced iPLA2-mediated activation of SOCs is strongly supported by a growing number of studies from different groups in multiple cell types. Intracellular application of CIF was shown to activate not only cat-SOC in SMCs (43), but also Ca2+-SOC (ICRAC) in Jurkat T lymphocytes (42, 46) and RBL cells (47, 48). The crucial role of iPLA2 in SOC activation was originally demonstrated in RBL cells, Jurkat T lymphocytes, SMCs, and platelets (24, 30), and confirmed in prostate cancer epithelial cells (14). It is important to mention that in the absence of functional iPLA2, its lysophospholipid products can activate Ca2+ influx mediated by both kinds of SOC channels (30): Ca2+-SOC in RBL cells and cat-SOC in SMCs. Together, these findings demonstrate that the pathway mediated by CIF, iPLA2, and lysophospholipids is involved in activation of both Ca2+-SOC and cat-SOC in growing numbers of cells, so all SOCs may be regulated by the same CIF- and iPLA2-dependent mechanism.

Can SOCs be activated by principally different mechanisms? Let us look at another mechanism that has been proposed for store-dependent activation of SOCs—the conformational coupling model (49, 34), which suggests a direct coupling of store-operated channel with inositol 1,4,5-trisphosphate (IP3) receptor (IP3R) (49, 34). Variations of this model have been discussed for more than a decade (34, 4951), and this idea gained strong momentum when structural and functional coupling of transient receptor protein C3 (TRPC3) channel and IP3R was demonstrated (5256). This is a very attractive model, and there was no surprise that it dominated the minds (and the studies) of many leading groups until a major surprise came from the studies of triple IP3R knockout DT40 cells that lack IP3R1, IP3R2, and IP3R3. In strong contradiction with a conformational coupling model, these cells appeared to have a normal capacitative Ca2+ influx mechanism (5759) activated by store depletion.

Accumulating evidence suggests that Ca2+ influx may be activated by different mechanisms coexisting in the same cells. In LNCaP human prostate cancer epithelial cells, Prevarskaya and colleagues (14) discriminated two currents with different activation modes and distinct molecular origin of the Ca2+-conducting channels. One current was activated by pure depletion of the stores (with thapsigargin and BAPTA) and was dependent on iPLA2, whereas another one was activated by IP3 and was insensitive to iPLA2, but was sensitive to manipulations that may disrupt conformational coupling of IP3R with the plasma membrane channels. The first one, clearly SOC, was dependent on expression of TRPC4, but not TRPC1, whereas the second one (activated by IP3 and dependent on conformational coupling with IP3R) was dependent on expression of TRPC1, but not TRPC4. The authors believe that these two channels are SOCs that are regulated by store depletion through two different pathways—CIF and conformational coupling. However, clear evidence that IP3R-operated channels may be activated by simple depletion of the stores without any "help" from IP3R is still lacking, and the question remains: Is simple depletion of the stores indeed required and sufficient for activation of this IP3R-operated channel to qualify it as a SOC?

To account for these new findings, I would like to propose an alternative interpretation (Fig. 1), and speculate that two distinct classes of Ca2+-conducting channels may exist in plasma membrane: SOCs, which are activated by depletion of Ca2+ stores through the CIF-iPLA2 pathway (no IP3 is needed); and IP3R-operated channels (IP3ROCs), which are activated by IP3R through a direct coupling mechanism (no store depletion is needed). The existence of two functionally separate pathways that activate distinct channels may explain why the store-operated Ca2+ influx pathway works in the absence of IP3Rs in DT40 cells (5759) and why expression of an IP3R mutant that does not release Ca2+ from the stores may restore IP3-induced Ca2+ influx in DT40 cells (60) (which in this case clearly occurs without store depletion). The existence of two apparently different Ca2+ influx pathways (one store-operated, the other operated by conformational coupling) is also in line with findings by Putney’s group (6163), who found striking differences in the channel’s conducting properties and demonstrated that TRPC3 can be a part of either SOC or IP3ROC, depending on the level of its expression.

The scheme in Fig. 1 illustrates the possibility of compartmentalization of the store-operated pathway in the areas away from receptors and other Ca2+ influx channels. It also illustrates the ability of cat-SOC to not only provide Ca2+ for refilling the stores, but also to trigger depolarization and activation of voltage-gated Ca2+ channels, which may be located far away from SOCs and provide Ca2+ influx in functionally different cellular compartments. This model may resolve many conflicting findings and interpretations and may give a new perspective on the diversity of Ca2+ influx pathways, all of which are important for cellular function.

Editor's Note: This Perspective is part of a series related to an E-Conference held at Science’s STKE. Invited participants were asked to provide Perspectives that summarized the ideas, conclusions, areas of controversy, and challenges for future work that emerged in the online discussion at;14.


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