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REGULATORS OF CA2+ SIGNALING IN MAST CELLS Potential Targets for Treatment of Mast-Cell Related Diseases?

and *.

National Institutes of Health, Bethesda, Maryland, USA. * Corresponding Author: Michael A. Beaven—Email:vog.hin.iblhn@mnevaeb

Mast Cell Biology: Contemporary and Emerging Topics edited by Alasdair M. Gilfillan and Dean D. Metcalfe.
©2010 Landes Bioscience and Springer Science+Business Media.
Read this chapter in the Madame Curie Bioscience Database here.

A calcium signal is essential for degranulation, generation of eicosanoids and optimal production of cytokines in mast cells in response to antigen and other stimulants. The signal is initiated by phospholipase C-mediated production of inositol 1,4,5-trisphosphate resulting in release of stored Ca2+ from the endoplasmic reticulum (ER) and Golgi. Depletion of these stores activates influx of extracellular Ca2+, usually referred to as store-operated calcium entry (SOCE), through the interaction of the Ca2+-sensor, stromal interacting molecule-1 (STIM1), in ER with Orai1(CRACM1) and transient receptor potential canonical (TRPC) channel proteins in the plasma membrane (PM). This interaction is enabled by microtubular-directed reorganization of ER to form ER/PM contact points or "punctae" in which STIM1 and channel proteins colocalize. The ensuing influx of Ca2+ replenishes Ca2+ stores and sustains elevated levels of cytosolic Ca2+ ions-the obligatory signal for mast-cell activation. In addition, the signal can acquire spatial and dynamic characteristics (e.g., calcium puffs, waves, oscillations) that encode signals for specific functional outputs. This is achieved by coordinated regulation of Ca2+ fluxes through ATP-dependent Ca2+-pumps and ion exchangers in mitochondria, ER and PM. As discussed in this review, studies in mast cells revealed much about the mechanisms described above but little about allergic and autoimmune diseases although studies in other types of cells have exposed genetic defects that lead to aberrant calcium signaling in immune diseases. Pharmacologic agents that inhibit or activate the regulatory components of calcium signaling in mast cells are also discussed along with the prospects for development of novel SOCE inhibitors that may prove beneficial in the treatment inflammatory mast-cell related diseases.

INTRODUCTION

The generation of a calcium signal is critical for activation of mast cells and blood basophils. This signal results from receptor-mediated activation of phospholipase (PL)C and the associated production of inositol 1,4,5-trisphosphate (IP3) which induces release of Ca2+ from stores in the endoplasmic reticulum (ER) and Golgi through Ca2+-conducting IP3-receptors (IP3R). Depletion of the Ca2+-stores activates influx of external Ca2+, a process commonly referred to as store-operated calcium entry or SOCE (reviewed in reference 1). One well characterized mechanism of Ca2+ influx via SOCE is the Ca2+-selective calcium-release activated calcium current (ICRAC) first described in RBL mast cells by Hoth and Penner.2,3 The influx of Ca2+ allows reuptake of Ca2+ into ER through a sarco/endoplasmic Ca2+-ATPase (SERCA) pump and thereby replenishes ER stores and sustains increases in concentration of cytosolic Ca2+ ([Ca2+]cyt), the essential signal for mast cell activation. [Ca2+]cyt is also dynamically regulated by extrusion of Ca2+ from the cell by a Ca2+-ATPase (PMCA) pump and ion-exchange transporters in the plasma membrane. The dynamics and spatial configuration of the calcium signal within the cell is further shaped by mitochondria which possess specialized mechanisms for Ca2+- uptake and efflux and a high capacity for calcium-buffering (Fig. 1). The spatial and temporal characteristics of the calcium signal, which may include calcium "puffs", "waves" and "oscillations", are thought to encode sub-signals for different cellular functions.

Figure 1. Calcium fluxes in stimulated mast cells.

Figure 1

Calcium fluxes in stimulated mast cells. An initial event is the release of Ca2+ through IP3 receptors (IP3R) from Ca2+ stores in ER (as depicted), Golgi and nuclear membrane (not depicted) into the cytosol following FcεRI (R) aggregation by antigen (more...)

In addition to IgE-specific antigens, other mast cell stimulants also induce PLC-mediated calcium signals. These stimulants include the growth factor KIT ligand, also referred to as stem cell factor (SCF),4 as well as agonists of G protein-coupled receptors such as adenosine,5-7 PGE2,8,9 the formyl peptide fMetLeuPhe,10 platelet activating factor,10 and C3a/C5a.11 Some mast cell activating ligands such as microbial Toll-like receptor (TLR) ligands and IL-33 can elicit modest production of cytokines without mobilizing calcium or causing degranulation but this production of cytokines is markedly enhanced by costimulation of cells with antigen which elicits synergistic costimulatory signals though calcium.12 Calcium signals thus enable degranulation,13,14 activation of PLA2 for the production of the eicosanoids,15 activation of the Ca2+/calcineurin/nuclear factor of activation of T-cells (NFAT) pathway for transcription of cytokine genes,12 or Ca2+-dependent cytoskeletal remodeling for chemotaxis (Fig. 1).11

The description of ICRAC prompted a prolonged search for an elusive ICRAC channel protein (CRAC). The essential components of CRAC were identified only recently as the Ca2+-channel protein Orai1 (also known as CRACM1) and its activating ER calcium-sensor, stromal interaction molecule-1 (STIM1). Before then, the nonselective Ca2+-conducting transient receptor potential canonical (TRPC) proteins were initially considered as candidates for CRAC but none of the TRPCs exhibited the exact characteristics or Ca2+-selectivity of ICRAC. Because expression of both STIM116,17 and Orai118-20 reconstituted ICRAC in all fidelity21-23 in various types of cells including mast cells, the pendulum of thinking has swung towards the notion that the activating interaction of STIM1 with Orai1 is the underlying mechanism for SOCE. There remains, nevertheless, an accumulating body of evidence that TRPCs participate in SOCE, possibly cooperatively with STIM1 and Orai1, in mast cells and other types of cells.1 As discussed in the next section, the participation of TRPCs would be consistent with observations several decades ago that other divalent metal ions are taken up by and can substitute for Ca2+ in the activation of mast cells.

In this chapter, we first describe the early studies of calcium and mast cells for reasons just noted. Subsequent sections provide descriptions of various organelles that regulate calcium signaling in mast cells. Although the contributions of ER, mitochondria and the plasma membrane are described separately for convenience of narrative, it should be emphasized that the final signature of calcium signal is determined by the coordinate actions of these three organelles (Fig. 1). The final and more speculative sections describe the functional outputs encoded by the calcium signal, the possible relevance of genetically-related defects in calcium signaling to mast cell related diseases and novel SOCE inhibitors developed for the purpose of treating allergic and autoimmune diseases.

EARLY AND RECENT OBSERVATIONS ON CALCIUM HOMEOSTASIS IN MAST CELLS: THE UNRESOLVED ISSUES

Mast cells and basophils were among the first experimental models to be used for the study of Ca2+-dependent secretion when it was discovered that extracellular Ca2+ was required for anaphylactic release of histamine from human leukocytes,24 rabbit basophils,25 and rat peritoneal mast cells.26 By then, histamine was shown to be a constituent of granules secreted from mast cells.27 Subsequent studies revealed that Sr2+ or Ba2+ could substitute for Ca2+ in supporting histamine release from rat peritoneal mast cells26,28 and that uptake of 45Ca2+ and 89Sr2+ correlated with the extent of this release.28,29 Such release, whether supported by Ca2+ or Sr2+, was effectively blocked by low concentrations of La3+.30,31 The conclusions drawn from these studies was that mast cell degranulation was dependent on substantial influx of Ca2+ through "Ca2+ channels" which can convey Sr2+.28

Later studies with Ca2+-sensitive fluorescent probes and 45Ca2+ in cultured RBL-2H3 cells indicated that degranulation was absolutely dependent on an increase in [Ca2+]cyt from ~0.1 to ~1 μM13 through release of Ca2+ from intracellular stores32-35 and influx of extracellular Ca2+.13 As in the earlier studies, this influx permitted entry of Sr2+ and other divalent metal ions.36 Influx was accompanied by substantial uptake of Ca2+ into IP3-sensitive and mitochondrial pools37,38 wherein intracellular Ca2+ increased from approximately 0.5 mM to about 2.5 mM which then decreased as [Ca2+]cyt subsided.32 Influx was dependent on maintenance of the polarity of the plasma membrane, presumably through efflux of K+,32,39 and was counterbalanced by extrusion of Ca2+ from the cell by an ATP-dependent mechanism.32,40

Studies in other types of cells identified ER as the source of IP3-releasable Ca2+ and IP3R41 as the channel for Ca2+-release.42 Reuptake of Ca2+ into ER was blocked by thapsigargin which was found to be selective inhibitor of SERCA.43,44 This action of thapsigargin results in spontaneous loss or "leakage" of Ca2+ from the ER store45,46 by a still undefined mechanism. Depletion of the ER pool, whether by thapsigargin or IP3, invariably leads to entry of Ca2+ into the cell. This feature led to the proposal by Putney in 1986, of "capacitative calcium entry" now generally referred to as SOCE,47 a process that is relevant to mast cells.38,48 As noted in the previous section, the characterization of ICRAC in mast cells by Hoth and Penner2,3 resulted ultimately in the identification of the STIM1/Orai1 as the operational components of ICRAC.

Nevertheless, the high capacity of influx mechanisms for Ca2+ and other divalent metal ions in mast cells are contrary to the known features of ICRAC or Orai proteins. We have proposed on the basis of knockdown and overexpression studies in RBL-2H3 cells that TRPC5, which can convey Sr2+, interacts with STIM1 and Orai1 to enhance influx of Ca2+ and, as a consequence, allow entry of Sr2+.49 An alternative proposal based on studies in RBL-2H3 cells and bone marrow-derived mast cells (BMMC) is that TRPCs, particularly TRPC1, initiate localized Ca2+ puffs that potentiate IP3R-mediated Ca2+-release from nearby ER stores.50 This potentiation leads to the generation of a calcium wave and ultimately oscillations, phenomena commonly associated with SOCE. As discussed in detail later, studies in other types of cells suggest that some TRPCs, including TRPC1 and TRPC5, form complexes with Orai proteins and STIM1to create SOCE channels whose conductances (ISOC) differ from those of ICRAC. The role of TRPCs in calcium signaling is controversial. One view is that CRAC channels derived from STIM1 and Orai1 are the exclusive SOCE channel. The other is that STIM1, TRPCs and Orai proteins also form SOCE channels with varying degrees of selectivity (e.g., refs. 51,52). This review reflects our opinion that the latter mechanism operates in mast cells.

INITIATION OF THE CALCIUM SIGNAL VIA PLC, IP3R AND SPHINGOSINE KINASES (SKS)

Receptor-Mediated Activation of PLCγ or PLCβ Results in SOCE

A role for PLC was evident from early studies with RBL-2H3 cells in which correlations were noted in the production of inositol phosphates, increase in [Ca2+]cyt and degranulation.53 The PLC isoforms involved differed according to the type of stimulant; PLCγ with antigen54,55 and PLCβ with ligands to G protein-coupled receptors.10,56 Stimulation through either FcεRI or G protein-coupled receptors resulted in release of Ca2+ from a common IP3/thapsigargin-sensitive pool which was assumed to be in ER.5,38,57 Recently, stochastic modeling using three-dimensional constructs of electron-microscopic images of RBL-2H3 cells, along with supporting data, fits well with the concept of release of Ca2+ from ER through activation of IP3Rs by IP3.58

RBL-2H3 cells, BMMC and human peripheral blood-derived mast cells express both PLCγ1 and PLCγ2.59-61 PLCγ1 resides primarily in cytosol of RBL-2H3 cells but then migrates to the plasma membrane where it localizes largely in actin-rich membrane ruffles after antigen stimulation.59 PLCγ2, in contrast, is associated with Golgi and plasma membranes and remains so after stimulation. Both isoforms are tyrosine phosphorylated and thus activated, following antigen stimulation. The pathways leading to PLCγ phosphorylation are complex and are not entirely clear. Induction of FcεRI aggregation by antigen initiates phosphorylation cascades that involve the Src kinases Lyn and Fyn as well as Syk tyrosine kinase, phosphorylation of adaptor proteins, recruitment of additional signaling molecules by these adaptors and ultimately production of IP3 by PLCγ. The adaptor proteins, linker for activation of T-cells (LAT) and SH2-containing leukocyte-specific protein of 76 KDa (SLP-76) are critical for recruitment of PLCγ1 and calcium signaling (for a more detailed account see reference 62). Another essential component of mast cell activation is phosphoinositide 3-kinase (PI3K) whose activity is regulated largely by Fyn through the adaptor protein, Grb2-associated binder-like protein 2 (Gab2).63 It is unclear, however, whether the PLCs are activated separately through different pathways. Differences have been noted in RBL-2H3 cells where phosphorylation of PLCγ1, but not PLCγ2, is suppressed by the PI3K inhibitor wortmannin.59 In these cells, PLCγ1 was assumed to play the predominant role as both antigen-induced IP3 production and degranulation are also inhibited by wortmannin. In BMMC and human peripheral blood-derived mast cells, the initial activation of PLCγ1 occurs independently of PI3K.61 Indeed the phosphorylation and activation of both PLCγ1 and PLCγ2 are resistant to wortmannin, are still apparent in BMMC that lack p85 PI3K subunits and appear to precede the activation of PI3K. Wortmannin partially inhibits degranulation leaving the possibility that PI3K mediates later signals for degranulation.61 The differential distribution of the two isoforms of PLCγ in RBL-2H3 cells could result theoretically in calcium signals with different signatures. Whether the PLC isoforms are regulated differently and play complimentary roles in calcium signaling in mast cells are issues that require further investigation.

The pattern of expression of PLCβ isoforms in mast cells varies. Of the three known PLCβ isoforms, only PLCβ3 is expressed in RBL-2H3 cells56,64 whereas PLCβ2 and PLCβ3 are expressed in BMMC.9 PLCβ is activated through receptors that engage either the pertussis-sensitive G protein, Gi,9 or the pertussis- and cholera- toxin insensitive G protein, Gq.6 Receptors that operate through Gs and adenylate cyclase are generally inhibitory. Some of the Gi/q-linked receptors undergo rapid desensitization such that IP3 production and calcium signal are transient and insufficient to promote functional responses.8,65 However, ligands to such receptors can markedly potentiate the functional responses to antigen because of synergistic signaling interactions provoked by the sustained calcium signal induced by antigen.65

Role of the Sphingosine Kinase (SK) Isoforms, SK1 and SK2

Sphingosine was first identified and so named by Thudichum in 1884 as a metaphor for the mythological riddle of the Sphinx.66,67 In some respects this is still true for calcium signaling.1,68,69 In the modern era, the SK product, sphingosine 1-phosphate (S1P), was proposed to complement the actions of IP3 in promoting SOCE, degranulation,70,71 and the production of eicosanoids and cytokines72 in mast cells. Both IP3 and S1P were considered essential for release of Ca2+ from intracellular stores70 with S1P promoting transient release and IP3 a more sustained release coupled to Ca2+-entry.71 However, a subsequent report suggests that S1P regulates primarily Ca2+-entry rather than release.72 Another ambiguity is that SK1 was claimed to be the predominant regulator of calcium signaling in one study71 and SK2 in another.72 An uncertainty is that S1P is released from stimulated mast cells73 and could act in an autocrine manner74 to increase [Ca2+]cyt via PLCβ-coupled S1P receptors.75 Potential upstream regulators of the SK/Ca2+-pathway include the Src kinases Lyn and Fyn,76 PLD1 and clathrin which is thought to facilitate transfer of the lipophilic S1P from the plasma membrane to ER.77 Unlike IP3, S1P is not freely diffusible in the cytosol68 and the Ca2+-channel(s) targeted by S1P have yet to be identified.69 Regardless of these unresolved issues, there is corroborative and extensive evidence that S1P and related sphingolipids are critical for mast-cell driven allergic reactions74,78-80 as discussed in detail in the chapter by Juan Rivera and Ana Olivera, Sphingosine 1-Phosphate and mast cell function.

Function and Regulation of IP3R in ER

IP3Rs are of three subtypes (designated 1, 2 and 3) and are expressed predominantly in the ER and to a lesser extent in nuclear reticulum (NR) and Golgi.81-85 The IP3Rs are usually restricted to particular subcellular locations. In RBL-2H3 cells, IP3R1 and IP3R2 are located in ER and NR whereas IP3R3 is located elsewhere.86,87 RBL-2H3 cells express ~14,000 tetrameric IP3Rs with IP3R2 being the predominant form (70% of total) and IPR1 and IPR3 constituting 10% and 20% of total IP3Rs.87 As in other types of cells,81 stimulation of RBL-2H3 cells results in redistribution of IP3R from a diffuse to clustered pattern in ER and NR.87 The relevance of clustering is unclear but it could signify association with sites of IP3 production58 or formation of signaling complexes, sometimes referred to as signalosomes, which may contain IP3R, TRPCs, receptors for activated C-kinase-1 (RACK1), STIM1 and Orai1 (see ref. 88 and citations therein).

IP3Rs form functional Ca2+ channels only after oligomerization to form homo- or hetero-tetramers.85,89 Interestingly, the same is true for Orai and TRPC proteins which also form functional channels only after tetramerization. Each IP3R subunit consists of a cytosolic N-terminal IP3-binding domain, a large intermediate modulatory domain and a C-terminal helical transmembrane-spanning domain which, in the tetrameric state, form part of the Ca2+ channel. The IP3-binding domain lies in close proximity to the channel pore to enable conformational changes that are sufficient for channel gating.85,89 The intermediate domain contains binding sites for Ca2+, calmodulin and other factors that regulate IP3R function.81,83,85 All three IP3Rs exhibit biphasic responses to Ca2+ in which IP3R activity is enhanced or diminished at low or high [Ca2+]cyt respectively90 by mechanisms that are still conjectural.1 Other regulatory factors include RACK1 and scaffolding proteins that may allow targeting of IP3R to strategic sites and formation of signaling complexes.83,85 IP3Rs are phosphorylated by multiple serine/threonine protein kinases creating potential positive feed-back loops to enhance Ca2+-release.85,91 The Src tyrosine kinases, Fyn in T-cells92 and Lyn in B cells,93 also phosphorylate and positively regulate IP3R but it is not known if this occurs upon activation of these same kinases in mast cells. Many aspects of the regulation of IP3R activity remain unclear as described in several recent reviews.83,84,89,91

IP3-SENSITIVE INTRACELLULAR Ca2+-STORES AND COUPLING TO SOCE CHANNELS

IP3-Releasable Ca2+ Stores

In addition to ER, IP3-releasable Ca2+ stores are present in NR94 and Golgi.95 The ER and NR form a contiguous Ca2+-pool of ~0.5 mM but Golgi forms a separate pool of ~0.3 mM Ca2+. Initial increases in [Ca2+]cyt are primarily due to release of Ca2+ from ER and Golgi whereas release from NR is largely confined to the nuclear space.94 All three structures contain the thapsigargin-sensitive SERCA pump that ensures recapture of cytosolic Ca2+ against a high concentration gradient (also see following section). The Golgi membranes contain, in addition, a thapsigargin-insensitive Ca2+-ATPase (SPCA) pump. The individual contributions of Golgi and ER to the calcium signal in mast cells are unknown but several IP3-releasable pools are discernable in RBL-2H3 cells.96 Two of these are thapsigargin-sensitive of which only one is directly linked to ICRAC. The other is a thapsigargin-insensitive store which is presumed to be dependent on a calcium ATPase other than SERCA for refilling of this Ca2+ store. Compartmentalization of Ca2+ stores in ER/Golgi is also suggested from the differential effects of IP3, thapsigargin and ionomycin on ICRAC dynamics in the RBL1 mast cell line.97 The nature of these pools or compartments is unclear but there is evidence that, in some types of cells, Ca2+ can diffuse throughout the lumen of ER and depletion of the entire ER store is required for SOCE whereas in other types, such as polarized liver cells, diffusion of Ca2+ is restricted and depletion of a limited region of ER is sufficient to activate SOCE.98 It is likely that SOCE is activated in RBL-2H3 cells by depletion of ER stores near the cell periphery as SOCE can be activated by just 1 nM thapsigargin,38 a concentration that is known to localize and act only in regions of ER in close proximity to the plasma membrane.99 This concentration of thapsigargin does not induce degranulation whereas more conventional concentrations of thapsigargin (e.g., 1 μM) produce a global depletion of ER stores and degranulation.38,99

Actin and microtubular interactions direct ER motility which is essential for regulation of calcium signaling and other cellular functions.100 This motility, as we shall discuss later, permits functional contacts of ER with Ca2+ channels in the plasma membrane. Depolymerization of microtubules or inhibition of the microtubular motors, kinesin or dynein, reduces SOCE.101,102 Unintended effects of pharmacologic agents on ER motility and calcium signaling should be considered in studies of mast cell activation and function.

Ca2+ Uptake and "Leakage" in ER

Uptake and "leakage" of Ca2+ across the ER membrane appear to be dynamically balanced in resting RBL-2H3 cells.103 The "Ca2+ leak" from ER is apparent by a relatively slow increase in [Ca2+]cyt in the absence of external Ca2+ following blockade of SERCA by thapsigargin. Subsequent provision of external Ca2+ results in a rapid and substantial increase in [Ca2+]cyt which is the classic hallmark of SOCE. The number of SERCA channels, as determined by thapsigargin binding, has been estimated as 1.6 million/RBL-2H3 cell.103 Of the three known SERCA proteins and their spliced variants, only SERCA2b and SERCA3 are found in mast cells104 where they codistribute with IP3R1, IP3R2 and calreticulin on density gradients.86 IP3R3 is the anomaly in that it does not appear to be associated with ER or the SERCAs.86 The SERCA proteins transport two Ca2+ ions for each ATP molecule consumed which permits efficient recapture of released Ca2+ from the cytosol and possibly ensures refilling of ER with minimal perturbation of [Ca2+]cyt when ER is in close proximity to SOCE channels.105 SERCA activity also enables Ca2+ oscillations in cells.106 The SERCAs are regulated directly by free Ca2+ within ER.107 The Ca2+ sensing mechanism, however, is uncertain but suggested mechanisms include interactions with calreticulin and calnexin,108 STIM1,109,110 and presenilins.111 Calreticulin and calnexin reside in the ER lumen and ER membrane respectively and are interacting proteins that are best recognized for their role in protein folding. Both proteins as well as the phosphorylation of calnexin are critical for maintenance of SERCA-dependent Ca2+ oscillations in Xenopus oocytes.108,112 It is unknown whether similar mechanisms exist in mast cells but it is notable that calnexin is prominently phosphorylated in antigen-stimulated RBL-2H3 cells.113

The nature of the ER "Ca2+-leak" protein is still a matter of debate (hence the question mark in Fig. 1). Proposed candidates include the presenilins,114,115 the translocon complex,116-118 and pannexin-1.119 The presenilins were reported to form Ca2+-permeable channels in bilayer vesicles whereas mutant presenilins that are thought to be responsible for enhanced calcium signaling in Alzheimer's disease lacked such activity.114,115 However, others report no abnormality in ER Ca2+ "leakage" in cells from such patients but have noted enhanced IP3-mediated release.120 The aberrant calcium signaling in Alzheimer's disease has been attributed to interactions of constitutively active mutant presenilins with IP3Rs.121 The evidence in total does suggest a role for the presenilins in regulating Ca2+ homeostasis in part because of the links to Alzheimer's disease and the presumed interactions of presenilins with SERCA111 and IP3R.122 Although presenilins are expressed and possibly contribute to calcium signaling in mast cells, their role has yet to be determined.1 Translocon, a protein-conducting channel in ER, can serve as a "leak pathway" for Ca2+117,123 and can activate SOCE116,124 when not engaged in protein synthesis.125 However, contrary data has led to the conclusion that it is normally closed and is irrelevant to the physiological calcium leak mechanisms.118 The pannexins, a recently described family of ubiquitous molecules analogous to gap junction connexins, form not only intercellular gap junction channels but also Ca2+-permeable channels in ER. Overexpression and knockdown studies implicate pannexin1 as a mediator of "Ca2+-leak" and an activator of SOCE "in addition to any other potential leak mechanism."119 Whether one or more mechanisms actually exist, leakage has the intrinsic properties of an ion channel by exhibiting monoexponential efflux of Ca2+ from ER which shuts off once calcium stores have reached about 7% of their normal level.126 Leakage is also in dynamic balance with ER uptake.58

The ER Ca2+-Sensors, STIM1 and STIM2

The absolute requirement for STIM1 and Orai1 for activating ICRAC, calcium signaling, degranulation and cytokine production in mast cells has been demonstrated in BMMC derived from STIM1 or Orai1 deficient mice.127,128 These mice also have attenuated IgE-dependent allergic responses. Both isoforms of STIM are known regulators of SOCE in a variety of cell types.16,17,20 Both isoforms are highly homologous and contain an N-terminal EF hand along with a sterile α-motif (SAM) located in the ER lumen, a single transmembrane domain and protein-interacting domains in their lumenal and cytoplasmic portions.16,17,129 The affinity of the EF-SAM domains for Ca2+ is appropriately set to sense the concentration of free Ca2+ in ER ([Ca2+]ER) and state of depletion of ER Ca2+-stores.130,131

When ER Ca2+ stores are full, STIM1 is diffusely distributed throughout the ER microtubular network101 but as these stores are depleted, STIM1 oligomerizes and migrates to peripheral ER "punctae" in close proximity to the plasma membrane where it can activate ICRAC.16,22,132 Mutating the STIM1 EF-hand results in constitutive localization of STIM1 in "punctae" and activation of ICRAC independently of store-depletion.132,133 Collectively these studies imply that on store depletion dissociation of Ca2+ from the EF-hand, which is mimicked by mutation of the EF-hand, results in oligomerization and relocation of STIM1. Rearrangement of ER with formation of "punctae" containing colocalized STIM1 and Orai1 is also evident in antigen-stimulated RBL-2H3 cells.134 Maximal colocalization coincides with the initial spike in [Ca2+]cyt with rapid reversal upon decay in [Ca2+]cyt and refilling of ER stores.

The generally accepted scenario from studies in RBL-2H3134-136 and other types of cells is that coiled-coil domains in STIM1 and Orai1 and the electrostatic interactions between these two molecules are critical for the association of these two molecules and the activation of ICRAC.1 The oligomerization and migration of STIM1 to the cell periphery is dependent on a coiled-coil and another domain (aa 233-450, human numbering) in the cytoplasmic C-terminal region of STIM1.135,137 Functional interaction with Orai1 is dependent on a minimal domain (aa 342-448) in STIM1 called the CRAC activating domain (CAD)138 which contains a short conserved basic sequence (aa 382-387) that is sufficient to activate SOCE in RBL-2H3 cells.136 It is postulated that neutralization of a C-terminal acidic coiled-coil domain of Orai1134,139 by CAD transmits a gating signal for SOCE. In support of this idea, amphiphilic molecules such as D-sphingosine and N,N-dimethylsphingosine inhibit not only IP3-mediated ICRAC140 but also the FRET-monitored interaction of STIM1 with Orai1 and Ca2+-influx.134 The proposed model was that the positively charged sphingosines, which flip to the cytoplasmic surface of the plasma membrane, neutralize the Orai1 acidic residues resulting in Orai1 homo-oligomerization and preclusion of STIM1. Although these findings may point to regulation of SOCE by sphingolipids, they exclude a direct role for SKs because D-sphingosine is a substrate and N,N-dimethylsphingosine is an inhibitor of SK, yet both have the same effect.

STIM1 also interacts with various TRPC channels, either individually or as heteromeric combinations with Orai,52,141,142 and may do so though intramolecular electrostatic interactions between complementary positively-charged residues in STIM1 and negatively-charged residues in TRPC1 or TRPC3. However, it is claimed that the coupling mechanisms for Orai and TRPC are different.142

STIM2 has not been studied as extensively as STIM1 and not at all in mast cells. The STIM isoforms differ markedly in their rates of oligomerization and dissociation which may reflect differences in their regulation of calcium signaling.143 The indications are that STIM2 tightly regulates basal [Ca2+]cyt and [Ca2+]ER as STIM2 migrates to peripheral punctae and activates Orai1 in response to relatively small decreases in [Ca2+]ER.129 In contrast, STIM1 comes into play with more profound store depletion as indicated in cells from mice with conditionally targeted alleles of STIM1 and STIM2.144 Deficiency of STIM1 severely impairs thapsigargin-induced SOCE in these cells whereas deficiency in STIM2 had much smaller effects. One model based on studies with ectopic STIM proteins and whole-cell dialysis views STIM2 as constitutively active under basal conditions and negatively regulated by high [Ca2+]cyt.145

MECHANISMS OF Ca2+ ENTRY (SOCE) AND EXPORT ACROSS THE PLASMA MEMBRANE

Ca2+ Entry via TRPC and Orai Proteins

TRPCs are a subset of a superfamily of TRPs which include TRPC, TRPM (melastatin), TRPV (vanilloid), TRPA (ankyrin), TRPP (polycystin) and TRPML (mucolipin).146 All seven members of the TRPC subfamily have been investigated as potential candidates for CRAC channels and certain TRPMs are thought to negatively regulate plasma membrane polarity which, as we discuss later, is essential for maintaining SOCE activity.

As noted earlier, none of the TRPCs exhibit the exact characteristics of ICRAC147,148 In particular, some TRPC channels conduct Sr2+ and other divalent metal ions in addition to Ca2+ and have single channel conductances several orders of magnitude greater than ICRAC. All TRPCs are activated as a consequence of activation of PLC, either through store depletion or the generation of diacylglycerol.146 Formation of a functional cation channel requires assembly of four TRPCs either as homomeric or heteromeric tetramers such as TRPC1 with TRPC3, TRPC4, TRPC5, or TRPC7 and TRPC3 with TRPC6 or TRPC7.149 The electrophysiological characteristics vary significantly according to the constituents of the complex.146 Each TRPC monomer consists of six transmembrane segments (S1-S6) with the N- and C-terminal regions located within the cell. The pore-forming loop between S5 and S6 form part of the ion channel. The TRPCs contain, in addition, several consensus binding domains in the C-terminal portion and several ankyrin repeats in the N-terminal region. Both the C- and N- terminals contain coiled-coil domains which are thought to be essential for oligomerization.150

Like IP3Rs, TRPCs interact with accessory proteins to form signaling complexes.149 The accessory proteins are thought to regulate the cellular destination and function of the TRPCs. They include proteins involved in cytoskeletal interactions, vesicular trafficking and calcium signaling such as calmodulin, immunophillins, PLC, IP3R, STIM1, PMCA and SERCA.149-151 The ankyrin regions of TRPC appear to account for strategic targeting in the plasma membrane. Some TRPCs appear to be positively regulated by IP3R through interaction with an IP3R consensus binding-domain in TRPC. One concept is that TRPCs not only mediate SOCE but, in conjunction with IP3Rs, also regulate the amplitude of the calcium signal in localized regions for specialized cellular functions.149,152

The Orai proteins are atypical cation channel with four transmembrane domains.18-21,23 Three mammalian Orai gene products have been identified in a wide variety of cells. All three contain a proline/arginine-rich region in the N-terminus and a putative C-terminus coiled-coiled domain.153 The selectivity filter of Orai1 is linked to acidic residues in the first and third transmembrane domains and the first loop segment. As noted, formation of a functional CRAC channel requires formation of tetramers of Orai1.154,155 Orai1 can also oligomerize with Orai2 and Orai3 to create CRAC channels each exhibiting modest differences in ion-selectivity and inhibition by elevated [Ca2+]cyt.156 These differences could provide additional flexibility to the regulation of calcium signaling but their physiological relevance has not been demonstrated. All three Orai proteins can be activated by STIM2 as well as by STIM1.145

Orai1 along with STIM1 were recognized as the elusive components underlying ICRAC through several lines of evidence.16-20 Most dramatic was the demonstration that a mutation of Orai1 was linked to a severe combined immune deficiency (SCID) that was associated with deficient Ca2+-influx in T-cells. This deficiency could be rectified by expression of wild type Orai1.18 Overexpression of Orai1 and STIM1 together, but not individually, in a variety of cells resulted in substantial ICRAC.21-23 The field is evolving rapidly and the reader should consult recent reviews on the subject,148,157-160 some focused exclusively on immunological cells,161-164 for more detailed information. We have already noted that STIM1 and Orai1 are absolutely essential for activation of mast cells in vitro and in vivo.127,128 Nevertheless, the properties of ICRAC and Orai proteins would not account for the permeability of mast cells to divalent metal ions and Ca2+ or the nonselective cation currents (ISOC) that have been recorded in activated RBL-2H3 cells.165,166 The explanation, we believe, is the interaction of less selective TRPC channels with Orai1 and STIM1. As noted earlier, knockdown of endogenous TRPC5, STIM1, or Orai1 individually with inhibitory RNAs substantially reduces influx of Ca2+ as well as degranulation in RBL-2H3 cells.49 Moreover, overexpression of Orai1 with STIM1 promotes constitutive influx of Ca2+ but not of Sr2+ whereas overexpression of TRPC5 with STIM1 promotes constitutive influx of both ions. Sr2+ is used here only as a diagnostic probe as it is physiologically irrelevant. The data suggest that Sr2+-permeable TRPC5 acts coordinately with Orai1 and STIM1 to allow Sr2+ to permeate and induce degranulation (Fig. 2).49

Figure 2. Antigen-induced entry of Sr2+ and Ca2+ via a STIM1/Orai1/TRPC complex.

Figure 2

Antigen-induced entry of Sr2+ and Ca2+ via a STIM1/Orai1/TRPC complex. Changes in cytosolic Ca2+ and Sr2+ were monitored by single cell imaging of fura 2-loaded RBL-2H3 cells. Cells were stimulated with antigen (Ag) in Ca2+-free medium except for the (more...)

In support of the view that TRPCs participate in SOCE, studies in various types of cells have demonstrated that Orai1 forms complexes with some TRPCs and in conjunction with STIM1 creates currents (ISOC) with properties distinct from ICRAC.49,167-169 Such interactions include TRPC1 or TRPC5 with Orai149,51,167,169 and TRPC3 or TRPC6 with Orai1, Orai2, or Orai3.168 Apart from electrophysiological recordings and ablation of SOCE currents by use of siRNA technology, there are no pharmacological diagnostic probes. Like ICRAC, ISOC is blocked by low concentrations (1 μM) of La3+ and 2-aminoethoxydiphenyl borate (2-APB).51 If Orai proteins interact not only among themselves but also with TRPCs this would add further flexibility to the calcium "tool kit" that is available to cells. The future challenge, nevertheless, is to demonstrate these various combinatorial arrangements actually result in specific outcomes.

Polarity of Plasma Membrane Regulates Ca2+-Entry

Although Ca2+-influx in mast cells is driven by the high concentration gradient of Ca2+ across the plasma membrane (about 1/10,000), it is also dependent on maintenance of the electrochemical polarity of the plasma membrane.170 Depolarization of the plasma membrane with high external K+ abolishes Ca2+-influx and degranulation.32 The mechanisms for setting basal membrane potential may vary among subpopulations of mast cells, but the mechanism for repolarization appears similar. Resting RBL-2H3 cells express an inwardly rectifying K+ channel, Kir2.1, which sets the membrane potential at about -80 mV171 whereas resting primary human cell lines have a membrane potential of about 0 mV with no demonstrable Kir current.172 All these cell lines depolarize following influx of Ca2+ and then repolarize by a mechanism attributed to K+ efflux through the Ca2+-activated iKCa3.1 (also known as iKCa1) potassium channel (Fig. 1).172-174 Blockade of iKCa3.1 impairs degranulation174 and chemotaxis.175 The presence of stem cell factor (SCF), interleukin (IL)-6, or IL-10 increases the expression of functional iKCa3.1 in human mast cells and the authors suggest that this could account for the enhanced reactivity of these cells to antigen.174 Chloride channels have also been implicated in regulating membrane polarity, Ca2+-influx and degranulation in mast cells. The contributions of these channels to mast cell activation are not well defined and the reader is referred to a more detailed discussion of this topic in a recent review.172

The nonselective Ca2+-activated cation channels, TRPM4 and TRPM5, are thought to be negatively regulate SOCE.176 Both promote influx of monovalent but not divalent cations in mast cells.177 TRPM4, in particular, has been identified as promoting membrane depolarization and limiting Ca2+ influx (Fig. 1) and activation of BMMC in vitro and in vivo. 178,179 This is evident from increased FcεRI-mediated Ca2+-entry, release of inflammatory mediators and chemotaxis in TRPM4-/- BMMC as well as increased severity of the acute phase of IgE-mediated cutaneous anaphylactic response in TRPM4-/- mice. On this basis, TRPM4 is suggested as a potential therapeutic target for allergic diseases178 but the prospects would depend on whether TRPM4 acts similarly in other types of cells. TM-58483, an activator of TRPM4, suppresses Ca2+ and cytokine production in lymphocytes.180

Export of Ca2+ from Cells via Ca2+-ATPase Pumps (PMCAs) and Ion Exchangers

The orchestration of the calcium signal requires not only influx of Ca2+ but also its extrusion from cells. Extrusion is accomplished actively through PMCAs and passively through Na+/Ca2+ ion exchangers (Fig. 1). However, because of their high conducting capacity, Na+/Ca2+ exchangers probably play the predominant role in Ca2+ extrusion once [Ca2+]cyt is elevated. The more metabolically demanding PMCAs may then finely tune [Ca2+]cyt towards basal levels.181

PMCA shares many of the same structural and functional features as the SERCAs in ER and SPCA in Golgi. All three belong to a large family of P-type ATPases which are so named because the reaction cycle involves formation of a phosphorylated intermediate.182 However in contrast to SERCA, the PMCAs contain an extended C-terminal tail and transport one Ca2+ ion for each ATP molecule consumed as opposed to two Ca2+ ions for SERCAs. Much has been deduced about the structure and mechanisms of these pumps from the recent determination of the crystal structure of SERCA.182,183 Four PMCA isoforms and many of their spliced variants, have been cloned. Each PMCA contains an ATP-binding domain and a critical aspartate residue which is phosphorylated during each cycle of Ca2+ transport. This phosphorylation cycle is regulated by a Ca2+/calmodulin-binding region in the C-terminal domains of the PMCAs and is inhibited at low [Ca2+]cyt and facilitated when [Ca2+]cyt is elevated.1 As is the case for IP3R and SERCA, PMCAs form multiprotein complexes within specialized membrane domains and, in this manner, PMCA activity may be modulated by protein kinases and acidic phospholipids particularly the inositol phospholipids, sphingosine and phosphatidyl serine.181,184 PMCAs can adapt rapidly to CRAC185 and other Ca2+ channel activities in the cell.181 PMCAs are concentrated in strategic locations such as the apical membranes of pancreatic and salivary gland cells.186,187 Microarray data suggest that human umbilical cord blood-derived mast cells express PMCA1 and PMCA4188 but, in general, the functions of individual PMCA isoforms are not well defined. Studies in knockout mice suggest that PMCA1 is a regulator of cellular calcium in most or all cells whereas PMCA2 and PMCA4 have specialized cell-specific functions.182

The Na+/Ca2+ exchangers not only enable rapid Ca2+ extrusion but may also decouple SOCE from the inhibitory effects of elevated [Ca2+]cyt. These exchangers are categorized as K+-independent (designated as NCX) or K+-dependent (designated as NCKX).189 Although both families of exchangers are bidirectional and are driven by the electrochemical Na+ and Ca2+ gradients across cell membranes, NCKX family members are also dependent on the K+ gradient.189 Under physiologic conditions the Na+/Ca2+ exchangers extrude Ca2+ in exchange for Na+ when [Ca2+]cyt is elevated but ion exchange can be reversed by low concentrations of external Na+. At normal external concentrations of Na+, the exchangers positively regulate influx of Ca2+ or Sr2+, increase in [Ca2+]cyt and degranulation in mast cells by minimizing Ca2+-dependent inhibition of SOCE channels.190-192 At low concentrations of external Na+, Ca2+ efflux is substantially reduced191 and Na+/Ca2+ fluxes appear to be closely correlated when external concentrations of Na+ are varied.190 This correlation is one indication of the prominence of Na+/Ca2+ exchange during mast cell activation. Whole cell patch-clamp recordings on RBL-2H3 cells and BMMC indicate that both K+-dependent and K+-independent Na+/Ca2+ exchangers (identified as NCKX3, NCKX1 and NCX3) operate during SOCE and that they may account for as much as 50% of the Ca2+ extruded from cells when [Ca2+]cyt is elevated.192 Another indication is that the calculated maximal rate of Ca2+ efflux is 129 μM/s for Na+/Ca2+ exchange versus 17.5 μM/s for PMCA in stimulated RBL-2H3 cells.58 In other types of cells Na+/Ca2+ exchangers operate in conjunction with PMCA and SERCA to regulate [Ca2+]cyt192 and, like PMCA and SERCA, they interact with numerous regulators.189 These include lipids, especially phosphatidylinositol 4,5-bisphosphate, as well as cytoskeletal, scaffolding and signaling proteins.

MITOCHONDRIA MODULATE CALCIUM SIGNALING

The dynamics of the calcium signal are also dependent on mitochondrial activity in all cells193,194 including mast cells.37,38 Three dimensional reconstruction of electron microscopic images of RBL-2H3 cells depict mitochondria as frequently surrounded by ER58 to form ER/mitochondrial junctions195 with access to ER SERCA pumps.196 This architecture facilitates rapid uptake of newly released Ca2+ into mitochondria.58 Indeed, IP3 induces incremental and coordinated Ca2+-release from ER and Ca2+-uptake into mitochondria in permeabized RBL-2H3 cells.196 In intact RBL-2H3 cells, transfer of Ca2+ to mitochondria is most efficient during Ca2+ oscillations where the peak [Ca2+]cyt appears to activate a mitochondrial Ca2+ uniporter.197 This uptake enables rapid depletion of ER stores and in some cells localization of the calcium signal to specific subcellular domains.193 Although mitochondria are not as intimately associated with the plasma membrane as ER in RBL-2H3 cells,58 studies in other cells suggest that mitochondria in the vicinity of CRAC channels maintain CRAC activity by minimizing localized elevations of [Ca2+]cyt that would otherwise inhibit CRAC activity.198,199 In polarized cells, such as pancreatic acinar cells, the positioning of mitochondria confines Ca2+ waves to the apical area.200

It was initially thought that mitochondrial uptake occurred exclusively through a mitochondrial Ca2+ uniporter (MCU) which operates at relatively high [Ca2+]cyt (i.e., 1-10 μM) but whose protein composition is still undefined.201 However, it is now apparent that a Ca2+/H+ antiporter, the leucine-zipper-EF-hand-containing transmembrane (Letm1) protein operates at much lower [Ca2+]cyt (100 nM or lower).202 MCU uptake is driven by a negative membrane potential maintained by the respiratory chain and is activated by calmodulin at high [Ca2+]cyt. This allows rapid uptake of Ca2+ particularly in the vicinity of Ca2+ channels and during calcium transients thus restricting increases in Ca2+ to specific cellular domains.193,203 Letm1, in contrast, permits slow entry of Ca2+ in exchange for H+ (1 for 1) at low [Ca2+]cyt and its activity is dependent on the electron transport chain. Letm1 thus enables mitochondria to decode subtle changes in [Ca2+]cyt and regulate ATP production without risk of Ca2+ overload and apoptosis.194 Mitochondrial uptake and, as a consequence, SOCE are impaired in RBL-2H3 cells by the mitochondrial respiratory chain inhibitor, antimycin A, in combination with the ATP synthase inhibitor, oligomycin.37

Total mitochondrial calcium can reach millimolar concentrations as a freely dissociable calcium phosphate (Ca3(PO4)2) complex although free Ca2+ concentrations in mitochondria ([Ca2+]m) remain at 0.5-2 μM regardless of total calcium-load.204 Egress of Ca2+ is mediated by the Na+/Ca2+ exchanger, NCX, which permits recycling of Ca2+ across the mitochondrial membrane.204 Mitochondrial Ca2+ influx and efflux reaches rapid equilibrium over a wide range of loading conditions to buffer external Ca2+ at 0.5-1.0 μM, the so called mitochondrial "set-point" for [Ca2+]cyt,205 which appears to be the case in RBL-2H3 cells.38 Enhanced mitochondrial NCX activity in patients with human mitochondrial type 1 deficiency results in reduced mitochondrial Ca2+ levels and function along with aberrant calcium signaling in cells from these patients.206

THE SIGNATURE OF CALCIUM SIGNALS AND FUNCTIONAL CONSEQUENCES IN MAST CELLS

Calcium signals in individual mast cells are generally apparent as a sustained increases or oscillations in [Ca2+]cyt. In RBL-2H3 cells, oscillations are of variable amplitude and duration and are usually superimposed on a rising then decreasing baseline of elevated [Ca2+]cyt.33 The oscillations are not dependent on transient changes in membrane potential nor are they induced by ionomycin33 or thapsigargin.38 In both RBL-2H3 cells and BMMC, the oscillations are preceded by a Ca2+ wave that often originates in cell protrusions.50 Ca2+-entry is required to sustain oscillations beyond the initial few oscillations.33 Localized application of immobilized antigen results in nearby repetitive Ca2+ puffs that are generated by Ca2+ release from stores without stimulating Ca2+ entry or formation of propagating waves.50 These results, in the context of studies in other types of cells,207,208 suggest that initial Ca2+ puffs result from IP3-induced release of Ca2+ from ER which then evolve into waves and regenerative oscillations on widespread replenishment of ER stores by SOCE.

The future challenge is to define if and how multifunctional cells, such as mast cells,209,210 encode calcium signals to promote a particular response or subset of responses. We have already noted that mast cell degranulation14, formation of the eicosanoid precursor arachidonic acid,15,211 chemotaxis,11 and production of at least some cytokines212-214 are dependent on SOCE. Yet under certain conditions mast cells can be stimulated to undergo chemotaxis11,215,216 or produce cytokines4 without degranulation. Preferential release of either histamine or eicosanoids has been noted with different stimulants80,217,218 and attributed to differences in the amplitude and duration of the calcium signal.218 Although not specifically documented, mast cell homing and proliferation are presumably dependent calcium signals, as is true for other types of cells. The explanation as to how mast cells preferentially release mediators or undergo chemotaxis without releasing inflammatory mediators may lie in part on the nature of costimulatory signals but responses that require extensive cell remodeling such as degranulation or chemotaxis may still require calcium signals with defined spatial configurations.

Examples are insufficient to determine whether such is the case. What is known is that transient Ca2+ oscillations generated by release of Ca2+ from intracellular stores without influx are unable to support degranulation in antigen-stimulated RBL-2H3 cells.219 However, sustained Ca2+ oscillations or global increases of [Ca2+]cyt supported by influx of external Ca2+ are required for degranulation.13,15,220 A similar tight dependency on SOCE was noted for the recruitment of protein kinase C and components of the ERK/PLA2/5-lipoxygenase pathway in RBL cells activated with thapsigargin15 or receptor agonists.220 Stimulants such as agonists of the adenosine A3221 and purinergic P2Y220 receptors elicit transient production of IP3 and release of stored Ca2+ without activating sustained influx or degranulation. A confounding observation is that Ca2+-entry and activation of ICRAC is an all-or-none reaction in individual cells regardless of concentration of stimulant.220 The authors conclude that the typical concentration-response curves for cell populations may reflect an increasing proportion of responding cells rather than variation in strength of signal within individual cells.

PHARMACOLOGICAL PROBES: SOCE INHIBITORS EMERGE AS POTENTIAL THERAPEUTIC AGENTS

Pharmacological probes that have been traditionally used to investigate calcium signaling include IP3R activators (adenophostins) and inhibitors (heparin and xestospongins), SERCA inhibitors (thapsigargin and cyclopiazonic acid) and SOCE inhibitors (2-aminoethoxydiphenyl borate (2-APB)) although none of these have therapeutic application. Recently SOCE or CRAC channel inhibitors have emerged as potential therapeutic agents in the treatment of allergic and other inflammatory immune diseases.222 The traditional inhibitors identified above were discussed in depth in a recent review1 and they are discussed here only so far as their actions pertain to mast cells. The CRAC/SOCE inhibitors are discussed in more detail because of their therapeutic potential.

Traditional Probes for Investigation pf IP3R, SeRCA and SOCE Channels

The adenophostins (A and B) and their synthetic derivatives223 are the most potent IP3R agonists described to date but, because they are cell impermeant and diffuse slowly in cytosol, their administration require patch-clamp techniques. Adenophostin A has almost a hundred-fold greater affinity for IP3R than IP3224 and induces quantal release of Ca2+,225 intracellular Ca2+ oscillations and activation of ICRAC.226 However, these actions are restricted to regions where adenophostin remains localized to suggest that Ca2+ oscillations and entry do not extend into regions beyond the range of activated IP3Rs.227 In RBL1 cells, adenophostin A can induce Ca2+ oscillations when Ca2+ entry into the cell is blocked by voltage clamp to indicate that the oscillations are regenerative that is, reuptake of Ca2+ into ER replenishes stores sufficiently for another cycle of release and reuptake.226 Activation of ICRAC by adenophostin A, as is true for thapsigargin or IP3, is substantially diminished by mitochondrial depolarization.199

There are no ideal inhibitors of IP3R-mediated Ca2+ release. The membrane-permeant macrocyclic xestospongins (B, C and D) from sponge inhibit IP3-elicited Ca2+-release without affecting IP3 binding228 but they have slow action and may inhibit SERCA in some types of cells.229,230 In RBL-2H3 cells, xestospongin C (3-10 μM) inhibits intracellular release and influx of Ca2+, depletion of intracellular stores by IP3 and degranulation.231 However, activation of SOCE after store-depletion with thapsigargin is unaffected.

The widely used SOCE activator, thapsigargin, was shown to be a mast cell activator232-234 before it was found to deplete ER Ca2+-stores by blocking SERCA-mediated reuptake of Ca2+ into these stores.47 In the absence of external Ca2+, thapsigargin induces a slow increase and then decrease in [Ca2+]cyt as stores become depleted. As is the case with antigen-stimulated Ca2+-deprived cells (Fig. 2), subsequent provision of Sr2+ or Ca2+ causes sustained influx of these ions in RBL-2H3 cells and BMMC. Use of this protocol and siRNA technology demonstrated that TRPC5 conducted both ions whereas Orai1 conducted only Ca2+ and that both channel proteins where activated by STIM1 following stimulation with either antigen or thapsigargin.49 Thapsigargin inhibits SERCA in a stoichiometric manner by tightly binding to a single site that is common to the SERCAs but not PMCAs.43,235 Thapsigargin has very high affinity for all three SERCA isoforms236 such that its action is virtually irreversible.43,237 The mycotoxin cyclopiazonic acid, in contrast, is a reversible and a less potent inhibitor of SERCA but, like thapsigargin, it suppresses SERCA Ca2+-ATPase activity. The net effects of thapsigargin and cyclopiazonic acid on RBL-2H3 cells and BMMC are similar in that both activate a SOCE pathway that is permeable to Ca2+ and other divalent metal ions38,48 which is impaired by microtubular disrupting agents.238 This impairment was attributed to the inability of ER to communicate with SOCE channels in the plasma membrane or, reinterpreted in the light of current knowledge, to disrupted communication between STIM1 in ER and Orai or TRPCs in the plasma membrane.

2-APB was first reported to inhibit IP3-induced Ca2+-release from stores without affecting IP3 binding but later studies indicated that it blocked IP3R-mediated SOCE239 as well.1,240 2-APB has a biphasic action in RBL1 cells and other types of cells.241 ICRAC is enhanced and then suppressed at, respectively, low (1-5 μM) and high (10 μM or greater) concentrations of 2-APB. Similar biphasic actions have been noted with 2-APB on overexpressed Orai proteins.242-245 2-APB also suppresses uptake and "leakage" of Ca2+ from ER pools and release from mitochondria but the compound can be a useful reagent "when used cautiously".246

Novel Inhibitors of CRAC and SOCE Channels

The importance of SOCE in regulating the immunological responses of mast cells, lymphocytes and other inflammatory cells has encouraged the development of selective inhibitors of SOCE as potential therapeutic agents for the treatment of allergic and autoimmune diseases. Much of the research has been conducted by the pharmaceutical industry using high-throughput screening procedures. One approach is based on fluorescence-based measurements of [Ca2+]cyt following depletion of intracellular stores by receptor agonists linked to IP3 production, thapsigargin, or cyclopiazonic acid. Another is based on whole cell patch-clamp technology which permits more precise characterization of SOCE inhibitors than fluorescent methods in that it can distinguish between ICRAC (i.e.,Orai) and TRPC channel activity and can exclude the possibility that the inhibitors block SOCE activity by inducing membrane depolarization.222 These distinctions have not always been recognized and the term "CRAC inhibitor" should be used exclusively for inhibitors identified as such on the basis of electrophysiological characteristics and the term "SOCE inhibitor" when this is not the case. Either type of inhibitor, however, should be equally interesting in terms of therapeutic potential (for an informative overview see ref. 222).

More selective compounds than 2-APB were discovered after a systematic investigation of 6,5-heterocyclic compounds by investigators at the Abbott and Astellas Pharma (formerly Yamanouchi Pharmaceuticals) laboratories. Ultimately a series of highly potent 3,5-bis(trifluoromethyl)pyrazole derivatives were developed that suppressed ICRAC. One such compound, BTP2 (otherwise known as YM58483 and now available commercially), selectively blocked thapsigargin-induced SOCE in Jurkat T-lymphocytes (IC50 = 150 nM).247 as well as IP3-evoked ICRAC in Jurkat and RBL-2H3 cells (IC50 = 2.2 and 0.5 μM, respectively).180 Interestingly, BTP2 also activates the membrane-depolarizing channel, TRPM4, at nanomolar concentrations and this action probably accounts for the potent BTP2 inhibitory effects on SOCE (as opposed to ICRAC) and the associated production of IL-2 in Jurkat cells.180 Unfortunately, similar comparisons were not reported for RBL-2H3 cells as BTP2 would appear to be useful in distinguishing between the contributions of CRAC and TRPM4 channels on SOCE and functional responses in mast cells. BTP2 also inhibits store-dependent Ca2+ and Sr2+ influx through expressed TRPC3 and TRPC5.248 Structurally similar inhibitors of SOCE and of IL-2 production in T-cells have been reported by Boehringer Ingelheim in a series of patent applications.(see ref. 222 for patent citations). BTP2 has proved effective in such models as mouse contact hypersensitivity,247 antigen-induced eosinophilia in rodent asthma models, mouse graft versus host disease249,250 and sheep red blood cell-induced delayed hypersensitivity in mouse. However, little is reported about its side-effects.

Other CRAC channel inhibitors have emerged from studies at Synta Pharmaceuticals. Of these, Synta 66 (GSK1349571A) was reported to be a relatively potent (IC50 = 1.4 μM) inhibitor of ICRAC in RBL-2H3 cells and thapsigargin-induced Ca2+ influx (i.e.,SOCE) in Jurkat T-cells without affecting TRPM4 and other channel functions.222 Synta 66 also caused a modest reduction of T-cell proliferation and concentration-dependent reductions in expression of T-bet, IL-2 and IL-17 in vitro in biopsy specimens from humans with inflammatory bowel diseases.251

Although, the published data are too sparse to evaluate the efficacy and specificity of the CRAC inhibitors, the number of patent applications indicate considerable interest in CRAC inhibitors for the treatment of inflammatory diseases.222 The identification of potent, selective inhibitors of these ion channels should be facilitated by the recent discovery of ORAI1 and STIM1 and new high-throughput ion channel inhibition assays.252 However, the current emphasis on CRAC/Orai inhibitors should not exclude TRPCs and TRPM4 as potential targets for reasons discussed throughout this review. Therefore, both fluorescence and electrophysiological approaches should be pursued. Certainly, the current search for new channel inhibitors might provide new opportunities for the treatment of mast cell-related diseases. Their inherent advantage would be their rapid action because of the immediacy of the calcium signal during the activation of mast cells. Nevertheless, undesired effects will always remain a paramount issue because of the ubiquity of SOCE in cell signaling and here targeted drug disposition would be crucial in developing effective drug therapy.

DISEASE CORRELATES

No mast cell-related disease has been directly linked to genetically-related defects in calcium signaling but other human diseases have been so linked. In addition to the presenilin mutations associated with Alzheimer's disease, other examples include loss-of function mutations of Orai118,253 and STIM1254 in SCID, inactivating mutations of SERCA1in Brody's disease of muscle,182 gain-of-function mutation of SERCA2 in Darier's skin disease,255 an inactivating mutation in Golgi SPCA1 in Hailey-Hailey skin disease,203 and spontaneous deafness-inducing PMCA mutations.182 While none of these mutations have been directly linked to atopic disease in humans, it has been inferred that the defects in Orai1 and STIM1 may lead to other immunodeficiency and autoimmune diseases254 and be expected to ameliorate allergic disease on the basis of studies in experimental animal models.127,128

In addition to the above, gain-of-function mutations in TRPM4 and TRPC6 results in familial heart block type256 and glomerulosclerosis,257,258 respectively. As noted previously, TRPM4 is implicated in the regulation of SOCE, degranulation and migration of mast cells178,179 but the impact of mutant TRPM4 on mast cell function has not been determined. TRPC6 is expressed in mast cells49 but its function there is unknown. Numerous diseases have been mapped to chromosomal loci containing TRP channel genes but await demonstration of direct linkages.259,260 Given the variety of genetically-related defects in calcium signaling in humans and the central role of calcium signaling in the activation of mast cells and other cells involved in inflammatory immune diseases, it seems a worthwhile to pursue the possibility that such defects may underlie allergic inflammatory disease in some subsets of patients.

CONCLUSION

Primary and cultured mast cell lines have been widely used for studies of calcium signaling over the past 40 years and we have learnt much about SOCE-dependent signaling from studies of these cells. Indeed, the mast cell will remain an ideal model for future research if mechanisms exist for encoding calcium signals for specific cell responses. If so, we need to understand how the activities of the various Ca2+ channels and sensors in different organelles are orchestrated to produce the appropriate calcium signal. Evidence points to the formation of signaling complexes embedded in specialized membrane-microdomains that facilitate the migration and interactions of channels and sensors at ER/PM and ER/mitochondrial junctions. Also unknown is whether additional flexibility in signaling is provided by the ability of Orai and TRPC isoforms to form various hetero-tetrameric combinations. These are generic questions applicable to many types of cells. There has been surprisingly little activity in regard to defects in calcium signaling in atopic and autoimmune diseases even though there are now well documented examples of genetic diseases related to defects in the operation of SOCE, SERCA, TRPM4 and NCX. We suspect that this topic as well as examination of the novel SOCE/CRAC inhibitors will be key topics for future research on mast-cell related diseases.

ADDENDUM

Since completion of this manuscript Srikanth et al (Nature Cell Biol 2010; 12:436-46) have described a CRAC regulator (CRACR2A) that might account for the suppression of CRAC activity by high [Ca2+]cyt. At basal [Ca2+]cyt CRACR2A enhances binding of STIM to Orai thereby promoting SOCE but it dissociates from the STIM/Orai complex at high [Ca2+]cyt and inhibits SOCE. Apparently, CRACR2A and calmodulin compete for the same Orai1 binding site which is consistent with the previously described inactivation of Orai1 by calmodulin.

ACKNOWLEDGMENTS

Our studies are supported by the intramural program of the National Heart, Lung and Blood Institute of the National Institutes of Health.

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