Acta Pharmacologica Sinica

Invited review

Acta Pharmacologica Sinica 2006 July; 27 (7): 813-820

Store-operated calcium channels and pro-inflammatory signals

Wei-chiao CHANG¹

Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK

¹Correspondence to Dr Wei-chiao CHANG.
Phn 44-18-6528-2177.
Fax 44-18-6527-2488.
E-mail wei-chiao.chang@physiol.ox.ac.uk
Received 2006-05-21
Accepted 2006-05-30
doi: 10.1111/j.1745-7254.2006.00395.x

Abstract

In non-excitable cells such as T lymphocytes, hepatocytes, mast cells, endothelia and epithelia, the major pathway for calcium (Ca²⁺) entry is through store-operated Ca²⁺ channels in the plasma membrane. These channels are activated by the emptying of intracellular Ca²⁺ stores, however,neither the gating mechanism nor the downstream targets of thesechannels has been clear established. Here, I review some of the proposed gating mechanisms of store-operated Ca²⁺ channels and the functional implications in regulating pro-inflammatory signals.

Key words

calcium channels; store-operated Ca²⁺ entry; capacitative Ca²⁺ entry; calcium signaling; mast cells

Extract

Note: Please read the complete full text with Figures and Tables at

Introduction
Cells use Ca²⁺ as a key messenger to regulate a broad spectrum of vital processes. Changes in cytoplasmic Ca²⁺ can trigger responses as diverse as exocytosis, muscle contraction, enzyme metabolism, gene transcription and cell proliferation^[1]. To increase cytoplasmic Ca²⁺ concentration, Ca²⁺ is either released from intracellular stores or enters the cell by crossing the plasma membrane. In excitable cells, like nerve and muscle, calcium (Ca²⁺) entry is achieved largely through opening the voltage-gated and ligand-gated Ca²⁺ channels^[2,3]. The role of these ion channels is well established and the identity of amino acids in channel properties and gating is well known^[2,3]. In non-excitable cells,the main mechanism of Ca²⁺ entryis a process known as "capacitative Ca²⁺entry" or "store-operated Ca²⁺ entry"^[4]. Non-excitable cells do not fire action potentials and voltaged Ca²⁺ channels are absent^[4]. Instead, store-operated Ca²⁺ entry is vital for driving most Ca²⁺-driven messengers. However, despite considerable research,neither the gating mechanism nor the molecular identity of thesechannels has been resolved. Here, I review some of the recent findings and theories of the store-operated Ca²⁺ entry pathway.

Store-operated Ca²⁺ entry/capacitative Ca²⁺ entry
The model of store-operated Ca²⁺ entry in non-excitable cells was first proposed in 1986^[5]. The fundamental idea of this model was that the Ca²⁺ influx pathway could be activated by the amount of calcium in the internal store. As the Ca²⁺ concentration falls, a signal is sent from the stores to open the Ca²⁺ channels in the plasma membrane (Figure 1). The first direct evidence in support of the basic tenet of this idea was identified by discovery of a Ca²⁺ current that was activated by store depletion. The underlying Ca²⁺ channels were called calcium release-activated calcium channels (CRAC) and this calcium selective current was called I_CRAC^[6].
Store-operated Ca²⁺ channels are the major route of Ca²⁺ influx in non-excitable cells and the best characterized store-operated current is I_CRAC. CRAC channels are non-voltage-gated channels that are very selective to Ca²⁺ (P_Ca2+/P_Na+>1000) and have an extremely small conductance for Ca^2+[7]. The current is large at negative potentials and approaches the zero current level at positive potentials (>60 mV)^[7]. CRAC channels require extracellular Ca²⁺ to maintain their activity. Removal of extracellular Ca²⁺results in a slow decline of channel activity^[8].
Pharmacology of store-operated Ca²⁺channels Store-operated Ca²⁺ entry can be evoked by any strategy that lowers the Ca²⁺ content of the stores^[6,7]. Physiologically, intracellular stores lose Ca²⁺ following a rise inthe levels of inositol 1, 4, 5-trisphosphate [Ins(1,4,5)P₃]_, which opens ligand-gated Ca²⁺ channels in the endoplasmic reticulum (ER) membrane. Experimentally, stores can be easily emptied following application of endoplasmic reticulum Ca²⁺ ATPase (SERCA) inhibitors like thapsigargin or exposure of the cytoplasm to high concentrations of Ca²⁺ chelators such as EGTA or BAPTA that interfere with Ca²⁺ store refilling and cause passive stores to empty. Other methods of emptying intracellular stores include dialyzing the cytosol with Ins(1,4,5)P₃or permeabilizing the ER membrane to Ca²⁺ by applying Ca²⁺ ionophores like ionomycin.
Establishing a link between ion channel activity and activation of physiological functions relies on the use of pharmacological inhibitors. Thus, the issue of how best to block store-operated Ca²⁺ channels is an important theme in this field. Several pharmacological agents, such as La³⁺, econazole and SK&F 96365 are known to inhibit store-operated Ca²⁺ channels. However, they can also block several other channels over a similar concentration range^[9]. Thus, they should not be considered specific inhibitors for store-operated Ca²⁺ channels. 2-Aminoethoxydiphenyl borate (2-APB), an InsP₃ receptor inhibitor, has become a popular tool to investigate store-operated Ca²⁺ channels^[10-12]. 2-APB is used as an InsP₃R antagonist, but growing evidence suggests that it is not simply an InsP₃receptorsblocker. For example, I_CRAC in mutant DT40 cells not expressing InsP₃receptorscan be blocked by 2-APB, indicating that targets other than InsP3 receptor are affected^[13,14]. Therefore, 2-APB seems to directly block the store-operated Ca²⁺ channels themselves. Another store-operated Ca²⁺ channel inhibitor is diethyl-stilbestrol. A synthetic estrogen agonist, diethylstilbestrol has been found to inhibit store-operated Ca²⁺ entry in human platelets, rat basophilic leukemia cells, and vascular smooth muscle cells but did not affect a whole-cell monovalent cation current mediated by TRPM7 channels^[15]. Trans-stilbene, a close structural analog that lacks hydroxyl and ethyl groups, had no effect on store-operated Ca²⁺ influx^[15].
Mitochondrial regulation of store-operated Ca²⁺ channels Mitochondria play an important role in production of ATP in eukaryotic cells. However, evidence has revealed that mitochondria can rapidly take up a great amount of calcium that has entered through different Ca²⁺ channels^[16-19]. Can store-operated Ca²⁺ channels be regulated by the mitochondria? An elegant series of experiments establishing how mitochondrial Ca²⁺ uptake regulates store-operated Ca²⁺ channels has come from work on rat basophilic leukaemia (RBL) cells and T lymphocytes^[20,21]. In RBL cells, mitochondria are also necessary for the activation of I_CRAC under physiological conditions of weak intracellular Ca²⁺ buffering. Whole cell dialysis with Ins(1,4,5)P₃ fails to activate any detectable I_CRAC unless mitochondria are in an energized state^[20,22]. Mitochondrial depolarization using electron transport chain blockers, such as antimycin A or rotenone, prevented I_CRACfrom developing, and the size of I_CRAC to thapsigargin could be increased by energized mitochondria^[20,22]. In T lympho-cytes, moreover, energized mitochondria reduced Ca²⁺-dependent slow inactivation, thereby prolonging the time-course of Ca²⁺ influx. Inhibition of mitochondrial Ca²⁺ uptake by CCCP or antimycin A enhanceCa²⁺-dependent inactivation of I_CRAC^[21]. Moreover, functional mitochondriaare required to sustain CRAC channel activity, and downstream transcription factor NFAT translocation^[21].

Mechanism of store-operated Ca²⁺ channel activation
The activation mechanism of store-operated Ca²⁺ channels is one of the most intriguing mysteries. In the past few years, several models have been proposed to explain the link between store emptying and Ca²⁺ influx. Although there is evidence to support each model, there is also evidence that can not be easily fitted into any. In this review, I focus on different activation models (Figure 2) of store-operated Ca²⁺ channels.
Diffusible messenger model Randriamampita and Tsien were the first to propose the existence of a small diffusible molecule that activated store-operated Ca²⁺ channels^[23]. This molecule was named calcium influx factor (CIF), and is released following Ca²⁺ store depletion and translocates to the plasma membrane to activate store-operated Ca²⁺ channels. CIF is a phosphorylated molecule that could be degraded by okadaic acid-sensitive protein phosphatases^[24]. CIF produced by either mammalian cells or yeast with depleted Ca²⁺ stores directly activates store-operated Ca²⁺ channels in vascular smooth muscle cells^[25], and is able to accelerate the development of I_CRACin Jurkat T lymphocytes and RBL-2H3 cells^[26,27]. Although recent work on CIF is encouraging, it is still not known how CIF activates store-operated Ca²⁺ channels. Further evidence in support of the CIF model has come from work in smooth muscle cells^[28]. Smani et al^[28] reported that calcium-independent phospholipase A₂was essential for CIF-mediated Ca²⁺ influx. In this model, CIF disassociates inhibitory calmodulin from calcium-independent phospolipase A₂ (iPLA₂), leading to activation of iPLA₂then LysoPLs, which in turn open store-operated Ca²⁺ channels in the plasma membrane^[28]. Importantly, both the pharmacological iPLA₂ inhibitor bromoenol lactone and antisense oligonucleotides directed against iPLA₂ suppress the activation of store-operated Ca²⁺ channels following either with thapsigargin or CIF^[28]. These recent studies support a role of iPLA₂and LysoPLs in the CIF model.
Conformational coupling model Berridge and Irvine^[29,30] first proposed a mechanism of connection between ER and store-operated Ca²⁺ channels that involves a direct protein_protein interaction. According to this model, Ins(1,4,5)P₃receptors in the ER could be physically associated to store-operated Ca²⁺ channels in the plasma membrane. Store emptying could change the conformation of Ins(1,4,5)P₃ receptors, which then regulates the opening of store-operated channels through protein_protein interaction. This idea of conformational coupling was indirectly supported by works on Ins(1,4,5)P₃ receptors and the canonical TRP family, which are candidates for store-operated channels^[31,32]. In HEK-293 cells, recombinant TRPC3 channels can be co-immunoprecipitated with Ins(1,4,5)P₃receptors^[33]. Kiselyov et al^[31,34] also showed that the N-terminal domain of type 1 Ins(1,4,5)P₃receptors is involved in the activation of TRPC3. Similarly, studies done in human platelets have revealed the interaction between TRPC1 and type II Ins(1,4,5)P3 receptors^[32]. However, there are some studies documenting that Ins(1,4,5)P₃ receptors are not essential for the activation of store-operated channels. For example, I_CRAC in mutant DT40 cells not expressing all three types of InsP₃receptors can stillbe activated by thapsigargin, indicating physical coupling might not be essential in the activation of CRAC channels^[35]. These findings fit with observations by other groups, all of which reported that heparin, an IP₃ receptor antagonist, did not interfere with the activation of I_CRAC in RBL cells or DT40 chicken B cells^[36_38]. Thus, in some cell types, conformational coupling between Ins(1,4,5)P₃receptor and store-operated channels might not be required for the activation of I_CRAC.
Vesicular fusion model The third model to explain the activation mechanism of store-operated Ca²⁺ channels is vesicular fusion. This hypothesis suggests that store emptying causes store-operated Ca²⁺ channels to be inserted into the plasma membrane using an exocytotic mechanism. Yao et al^[39] first reported the vesicular fusion model in Xenopus oocytes. They found I_CRAC was disrupted by overexpression of a mutant of SNAP-25, indicating functional SNAP-25 is necessary to activate store-operated Ca²⁺ current^[39]. In rat megakaryocytes, the vesicular transport inhibitor primaquine was found to block the development of I_CRAC, suggesting the involvement of exocytotic mechanisms^[40]. In HEK-293 cells, Alderton et al^[41] reported that direct microinjection of botulinum neurotoxin A and tetanus neurotoxin, which cleaves SNAP-25 and specifically hydrolyzes vesicle-associated membrane protein 2, respectively, impaired store-operated Ca²⁺ entry. However, there is evidence indicating that SNAP-25 might not be involved in the activation of store-operated Ca²⁺ entry. The major challenge to the vesicular fusion model came from studies on the expression of SNAP-25 in nonexcitable cells. Scott et al^[42] found that neitherHEK-293 nor COS-1 cell lysates had detectable levels of SNAP-25. In contrast, both HEK-293 and COS-1 cells express highlevels of botulinum neurotoxin A-insensitive SNAP-23 protein. In spite of the overexpression of mutant SNAP-23, store-operated Ca²⁺ entry was unaf-fected. In RBL cells, Bakowski et al^[43] reported that recombinant protein alpha-SNAP1-285, an inhibitor of exocytosis, inhibited vesicular fusion but had no effect on the activation of I_CRAC. Hence, vesicular fusion does not seem to be involved in the activation of I_CRAC .
Calcium sensor model In 2005,some exciting results came from Roos et al^[44] in the elusive mechanism of store-operated Ca²⁺ channels. They applied an RNAi-mediated silencing screen to 170 genes in Drosophila S2 cells, including a number of transientreceptor potential genes, and used thapsigargin-evoked Ca²⁺ entry as a marker for store-operatedchannels. One gene coding for a protein called stromal interaction molecule (STIM) significantly reduced thap-sigargin-induced store-operated Ca²⁺ influx. They also comfirmed that STIM1 knockout in Jurkat T cells was abolished in I_CRAC.^[44]. Similarly, after screening 2,304 proteins, Liou et al^[45] identified two proteins, STIM1 and STIM2, that are essential for maintaining the store-operated Ca²⁺ entry in HeLa cells.
The NH₂-terminal domain of STIM1 contains an a helices structure called EF hand motif, and a protein_protein interaction domain called the sterile a motif (SAM)^[45]. Because of the EF hand motif, STIM1 is likely to be within the lumen of ER. STIM1 might function as the calcium sensor within stores^[45]. By transfecting fluorescent fusion protein to detect the localization of STIM1, Liou et al^[45] reported the redistribution of YFP-STIM1 into puncta near plasma membrane was triggered by thapsigargin-induced store depletion. Interestingly, when the calcium-binding aspartic acid residue in the EF hand motif was mutated to alanine, store emptying failed to trigger any store-operated Ca²⁺ influx^[45].
Zhang et al^[46]were the first to report that stores depletion results in the translocation of endogenous STIM1 from ER to plasma membrane. They showed that mutation of the EF hand motif that mimics store emptying triggered the activation and translocation of store-operated Ca²⁺ channels^[46]. Further evidence supporting the STIM1 model showed that overexpression of STIM1 resulted in a substantial increase in I_CRAC and mutants in the EF hand motif and C terminal of STIM1 altered the basic features of CRAC channels^[47]. The study indicates that, in addition to being a calcium sensor within ER, STIM1 within the plasma membrane might function as a regulatory component of store-operated Ca²⁺ channels^[47]. Thus, a new model proposes that STIM1 is located in the membrane of ER when stores are full. Once stores are empty, Ca²⁺ dissociates from the EF hand motif of STIM1, and STIM1 translocates to plasma membrane to activate CRAC channels. More data supports the involvement of STIM1 in the regulation of store-operated Ca²⁺ channels. Thus, the goal for understanding the mechanism of store-operated Ca²⁺ channels activation seems to be a real possibility.

Physiological function of store-operated Ca²⁺ channels
There is growing evidence for a role of store-operated Ca²⁺ influx in human disease. Severe combined immuno-deficiency^[48,49]and acute pancreatitis^[50,51] have been linked to a failure of store-operated Ca²⁺ entry. Actually, the increase of intracellular Ca²⁺ through CRAC channels can regulate several inflammatory processes. This review will focus on studies over the past several years that have been aimed at understanding the activation of pro-inflammatory signals such as transcription factor nuclear factor kB (NF-kB)^[52-54], nuclear factor of activated T cells (NF-AT)^[52-54], endothelial nitric oxide synthase (eNOS)^[55], and leukotrienes^[56] by store-operated Ca²⁺ channels.
NF-kB and NF-AT These two transcription factors play important roles in immunity, cell proliferation and proinflammatory cytokine gene activation^{[52-54,57-59]}. NF-kB is considered to be a pro-inflammatory initiator that can be activated by different stimuli such as lipopolysaccharide^[60,61], ER stress^[62]. Decoy receptor 3 signalling^[63] , tumor necrosis factor^[58,59] and variations of the Ca²⁺ oscillations ampli- tude^[52-54]. Similarly, NF-AT is a familyof transcription factors that regulate gene expression during the immune response. The activation of NF-AT is tightly regulated by the Ca²⁺/calmodulin-dependent serine phosphatase calcineurin. In resting cells, phosphorylated NF-AT localizes in thecytoplasm but, after stimulation by calcium rise, calcineurin is activated, resulting in dephosphorylation of NF-AT. NFA-T translocates to the nucleus and stimulates gene transcription^[64-66]. Delmetsch et al^[52] first reported the involvement of Ca²⁺ oscillations through CRAC channels in the regulation of transcription factors NF-AT, Oct/Oap and NF-kB in T cells. Different frequencies of Ca²⁺ oscillations resulted in different molecular mechanisms for transcription factor activation^[52-54]. For example, high frequency of Ca²⁺ oscillations activated all three transcription factors, but low frequency Ca²⁺ oscillations only induced NF-kB activation. The changes in Ca²⁺ oscillations have been extended to control target gene activation, as well as to induce downstream immune response and inflammation. In Jurkat T cells, a sustained Ca²⁺ influx through CRAC channels is criticalfor transcription of NF-AT and the expressionof the interleukin (IL)-2 gene^[52-54]. YM-58483, a pyrazole derivative,potently inhibited thapsigargin-induced Ca²⁺ entry, NF-AT transcriptional activity and IL-2 production, but not AP-1-driven promoter activity, indicating that Ca²⁺ entry is able to drive different types of transcription factors^[67].
eNOS An increase in vascular permeability is an important sign of acute inflammatory process. Several mediators, such as histamine, bradykinin, prostaglandins and nitric oxide are kown to be involved in vascular permeability changes^[68]. eNOS is a calcium/calmodulin-dependent enzyme constitutively expressed in endothelial cells. eNOS-derived nitric oxide has an important role in some of the features of inflammation, such as cell rolling, vascular permeability and angiogenesis^[68]. In human endothelial cells, eNOS can be regulated by lysophosphatidylcholine^[69-71] through a dynamic interaction between casein kinase 2 and serine/threonine phosphatase 2A in Sp1 binding activity. In pulmonary artery endothelial cells, the SERCA inhibitor thapsigargin can activatenitric oxide production^[72]. However, it is not known whether this activation is caused by Ca²⁺ release from intracellular stores or Ca²⁺ influx through store-operated Ca²⁺ channels. The first example of how store-operated Ca²⁺ influx can activate eNOS came from Lin et al^[73]. Their results indicated that membrane-associated wild-type eNOS enzymatic activity is more sensitive to Ca²⁺ entry through store-operated Ca²⁺ channels than the release from intracellular stores. Because the localizationof wild-type nitric oxide synthase is very close to store-operated Ca²⁺ channels, this co-localization could contribute to the rapid activation of nitric oxide synthase by Ca²⁺ entry^[73] .
Arachidonic acid and leukotrienes In rat basophilic leukemia cells, Ca²⁺ entry through CRAC channelsdrivered exocytosis^[74]. Among the influentialmolecules released from mast cells are the leukotrienes that regulate a variety of inflammatory reactions^[75]. Chang and Parekh^[56] first described the involvement of CRAC channels in the regulation of pro-inflammatory signals by arachidonic acid and leukotriene C₄in RBL cells. Transient activation of CRAC channels following a 4 min stimulationby thapsigargin was sufficient to generate a significant increasein pro-inflammatory signals. Calcium influx through CRAC channels, but not calcium release from intracellular stores, stimulated arachidonic acid production^[56]. Arachidonic acid can be metabolized by 5-lipoxy-genase enzyme, leading to the formation of leukotrienes. In the regulation mechanism of LTC₄ secretion, calcium entry through CRAC channels activates extracellular signal regulated kinase (ERKs) within minutes and this is necessary for stimulation of cPLA₂^[76]. Ca²⁺ entry activates ERK indirectly, via stimulation of calcium-dependent protein kinase C isozymes a and bI ^[76]. Following opening of CRAC channels, protein kinase C isozymes a and bI translocate from the cytosol to plasma membrane. Acute inhibition of these isozymes or down regulation following chronic exposure to phorbol ester prevents Ca²⁺ entry from activating ERK, cPLA₂ and LTC₄^[76]. Although phorbol ester (PKC activator) stimulation resulted in strong ERK phosphorylation, this was not associated with any arachidonic acid release nor LTC₄ secre-tion. Therefore, activation of PKC and subsequent phosphorylation of ERK1/2 in the absence of a Ca²⁺ signal is not sufficient to activate cPLA₂. Instead, both Ca²⁺ and PKC/ERK are needed. Neither stimulates alone, in the absence of the other, can trigger arachidonic acid and LTC₄ secretion^[76]. Importantly, mitochondrial depolarization, by impairing Ca²⁺ entry throughCRAC channels, suppressed the phosphorylation of ERK, releaseof arachidonic acid and downstream LTC₄secretion. The resultsestablish the importance of mitochondrial regulation of CRACchannel activity in determining subsequent downstream pro-inflammatory molecules^[56].

Conclusion
Store-operated Ca²⁺ channels have an essential role in the short-term and long-term regulation of the inflammatory process. Inlight of the fact that NF-kB, NF-AT, eNOS activation and LTC₄ secretion are very potent pro-inflammatory mediators and have been linked to chronic inflammatory disease such as arthritis, atherosclerosis and asthma, CRAC channels could be a rational therapeutic target for treating such disorders.

Acknowledgements
I am grateful to Prof Anant PAREKH for reading thispaper, and Wan-chen HUANG for help with the figures. Dr Wei-chiao CHANG is in receipt of an ORS studentship.

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