Store-operated Ca2+ entry: a STIMulating stOrai

doi:10.1016/j.tibs.2006.09.007

Trends in Biochemical Sciences

Volume 31, Issue 11, November 2006, Pages 597-601

https://doi.org/10.1016/j.tibs.2006.09.007 Get rights and content

Store-operated Ca²⁺ entry (SOCE) mediates much of the Ca²⁺ entry evoked by receptors that stimulate phospholipase C. However, for 20 years, the plasma membrane Ca²⁺ channel and the signal linking its activation to loss of Ca²⁺ from the endoplasmic reticulum (ER) have eluded detection. But the search might now be over. Two proteins, STIM1 (the ER Ca²⁺ sensor) and Orai1 (the Ca²⁺ channel), have recently been identified as the missing links in SOCE.

Section snippets

The birth of store-operated Ca²⁺ entry

Bob Michell first proposed a causal link between receptor-stimulated hydrolysis of phosphoinositides and Ca²⁺ signals [1]. He acknowledged a role for intracellular sources of Ca²⁺, but the link between phospholipase C (PLC) activity and Ca²⁺ entry across the plasma membrane (PM) held most of his attention. The discovery, in 1983, that inositol (1,4,5)-trisphosphate [Ins(1,4,5)P₃] stimulates Ca²⁺ release from the endoplasmic reticulum (ER) identified the link between PLC and intracellular Ca²⁺

STIM1 is the Ca²⁺ sensor

After 20 years of searching it is remarkable that two independent groups should simultaneously identify the Ca²⁺ sensor that links the ER to activation of SOCE. In a siRNA screen of >2000 proteins with known signalling motifs, Liou et al. [8] identified STIM1 (stromal-interaction molecule 1) and STIM2 as essential components of SOCE in HeLa cells. Although STIM1 and STIM2 are similar, differing primarily in the lengths of their N- and C-terminal tails, other groups find only STIM1 knockdown to

Orai proteins form the missing channel

Driven by what proved to be an illusory parallel between PLC-evoked Ca²⁺ entry in insect photoreceptors and SOCE, relatives of the TRP channels that mediate responses to light in insects emerged as the first serious candidates for SOCE channels. Twenty years on, mammalian TRP proteins are established as a family of cation channels regulating many important physiological functions and implicated in many diseases, but their relationship with SOCE is, at best, confusing. Despite often compelling

How do the players play?

Within months of their discovery, Orai1 and STIM1 (and their homologues in Drosophila) are accepted as essential components of SOCE: Orai1 forms the channel and STIM1 is the sensor of ER Ca²⁺ content 8, 9, 10, 11, 13, 14, 17, 18, 19, 23, 24, 25. The other mammalian homologues of Orai1 (Orai2 and Orai3) also seem to form SOCE channels [11], whereas only STIM1 (but probably not STIM2) forms the Ca²⁺ sensor. Both Orai1 and STIM1 are required for SOCE, yet overexpression of either alone 9, 10, 11,

Not the last word

CRAC is cracked, but questions remain. Do TRP proteins have anything to do with SOCE [29]? If Orai1 is such a universally important component of the SOCE channel, why does its almost complete inactivation in SCID patients and accompanying loss of SOCE in many cell types [21] cause symptoms that are restricted primarily to lymphocytes? And why should the electrophysiological properties of SOCE differ between cells [6]? What are the roles of Orai2, Orai3 [11] and STIM2? Does STIM1 have other Ca²⁺

Acknowledgements

Work from the author's laboratory is supported by the Wellcome Trust and BBSRC. The need severely to limit the number of references necessitated omission of many important papers in favour of recent reviews.

Glossary

Ca²⁺-release-activated Ca²⁺ current modulator 1 (CRACM1): Synonym of Orai1.
Ca²⁺-release-activated Ca²⁺ current (I_CRAC): The most thoroughly characterized (but not the only) current activated by depletion of stores. It is selective for Ca²⁺, inwardly rectifying and has a low single-channel conductance.
Orai1: Product of the human gene FLJ14466 on chromosome 12. It comprises 301 residues, with four predicted transmembrane domains within the PM, and cytosolic N and C termini (see Figure 2). It forms an

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ZnR-mediated relaxation response of human submucosal arterioles and the mesenteric arterioles from wide-type (WT), ZnR^-/- and TRPV4^-/- mice were determined by a Mulvany-style wire myograph. The perfused vessel density (PVD) of mouse mesenteric arterioles was also measured in in vivo study. The expression of ZnR in arterioles and vascular endothelial cells (VEC) were examined by immunofluorescence staining, and its function was characterized in VEC by Ca²⁺ imaging and patch clamp study.
ZnR expression was detected on human submucosal arterioles, murine mesenteric arterioles and VEC but not in ZnR^-/- mice. ZnR activation predominately induced endothelium-dependent hyperpolarization (EDH)-mediated vasorelaxation of arterioles in vitro and in vivo via Ca²⁺ signaling, which is totally different from endothelium-dependent vasorelaxation via Zn²⁺ (_cyt) signaling reported previously. Furthermore, ZnR-induced vasorelaxation via EDH was significantly impaired in ZnR^-/- and TRPV4^-/- mice. Mechanistically, ZnR induced endothelium-dependent vasorelaxation predominately via PLC/IP₃/IP₃R and TRPV4/SOCE. The role of ZnR in regulating Ca²⁺ signaling and ion channels on VEC was verified by Ca²⁺ imaging and patch clamp techniques.
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Intracellular Ca2+ signaling is a fundamental regulator of megakaryocyte (Mk) and platelet function through modulation of several intracellular pathways.14-18 Store-operated calcium entry (SOCE) is a well-described mechanism regulating Ca2+ entry from the extracellular space following endoplasmic reticulum (ER) store depletion.19 We and other investigators have previously described the expression and function of SOCE in Mks and platelets.16,20-22
Hemostatic abnormalities and impaired platelet function have been described in patients affected by connective tissue disorders. We observed a moderate bleeding tendency in patients affected by collagen VI–related disorders and investigated the defects in platelet functionality, whose mechanisms are unknown. We demonstrated that megakaryocytes express collagen VI that is involved in the regulation of functional platelet production. By exploiting a collagen VI–null mouse model (Col6a1^−/−), we found that collagen VI–null platelets display significantly increased susceptibility to activation and intracellular calcium signaling. Col6a1^−/− megakaryocytes and platelets showed increased expression of stromal interaction molecule 1 (STIM1) and ORAI1, the components of store-operated calcium entry (SOCE), and activation of the mammalian target of rapamycin (mTOR) signaling pathway. In vivo mTOR inhibition by rapamycin reduced STIM1 and ORAI1 expression and calcium flows, resulting in a normalization of platelet susceptibility to activation. These defects were cell autonomous, because transplantation of lineage-negative bone marrow cells from Col6a1^−/− mice into lethally irradiated wild-type animals showed the same alteration in SOCE and platelet activation seen in Col6a1^−/− mice. Peripheral blood platelets of patients affected by collagen VI–related diseases, Bethlem myopathy and Ullrich congenital muscular dystrophy, displayed increased expression of STIM1 and ORAI1 and were more prone to activation. Altogether, these data demonstrate the importance of collagen VI in the production of functional platelets by megakaryocytes in mouse models and in collagen VI–related diseases.
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The Orai family (Orai1, Orai2 and Orai3) of proteins, first identified in 2006,1–5 are plasma membrane proteins which share no homology with any other known calcium channel family.
The proteins Orai1 and STIM1 control store-operated Ca²⁺ entry (SOCE) into cells. SOCE is important for migration, invasion and metastasis of MDA-MB-231 human triple negative breast cancer (TNBC) cells and has been proposed as a target for cancer drug discovery. Two hit compounds from a medium throughput screen, displayed encouraging inhibition of SOCE in MDA-MB-231 cells, as measured by a Fluorescence Imaging Plate Reader (FLIPR) Ca²⁺ assay. Following NMR spectroscopic analysis of these hits and reassignment of their structures as 5-hydroxy-5-trifluoromethylpyrazolines, a series of analogues was prepared via thermal condensation reactions between substituted acylhydrazones and trifluoromethyl 1,3-dicarbonyl arenes. Structure-activity relationship (SAR) studies showed that small lipophilic substituents at the 2- and 3-positions of the RHS and 2-, 3- and 4-postions of the LHS terminal benzene rings improved activity, resulting in a novel class of potent and selective inhibitors of SOCE.
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The Orai1 Ca²⁺ permeable ion channel is an important component of store operated Ca²⁺ entry (SOCE) in cells. It’s over-expression in basal molecular subtype breast cancers has been linked with poor prognosis, making it a potential target for drug development. We pharmacologically characterised a number of reported inhibitors of SOCE in MDA-MB-231 breast cancer cells using a convenient Fluorescence Imaging Plate Reader (FLIPR) assay, and show that the rank order of their potencies in this assay is the same as those reported in a wide range of published assays. The assay was also used in a screening project seeking novel inhibitors. Following a broad literature survey of classes of calcium channel inhibitors we used simplified ligand structures to query the ZINC on-line database, and following two iterations of refinement selected a novel Orai1-selective dichlorophenyltriazole hit compound. Analogues of this were synthesized and evaluated in the FLIPR assay to develop structure–activity relationships (SAR) for the three domains of the hit; triazole (head), dichlorophenyl (body) and substituted phenyl (tail). For this series, the results suggested the need for a lipophilic tail domain and an out-of-plane twist between the body and tail domains.
The effect of bradykinin on the electrical activity of rat myenteric neurons
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A quite unexpected finding in the present study was the delayed effect of bradykinin resulting in a 2nd peak of electrical activity (Fig. 2) or cytosolic Ca2+ concentration (Fig. 9A), which often was observed several minutes (e.g. 10 min after the initial peak in the original recording of Fig. 6A) after the initial response has faded. At first glance, this might resemble the typical biphasic Ca2+ response observed after stimulation of Gq-protein coupled receptors, which after IP3-mediated depletion of intracellular Ca2+ stores (registered by proteins of the STIM family in the endoplasmic reticulum) evokes an influx of extracellular Ca2+ via store-operated Ca2+ channels in the plasma membrane (Taylor, 2006). However, the delay between the initial response and second peak observed here is much too long to be explained by such a mechanism and the ineffectiveness of 2-APB to inhibit the bradykinin-induced rise in the cytosolic Ca2+ concentration (Fig. 8) gives no hint for the participation of IP3 receptors.
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Citation Excerpt :
In particular, the mRNAs of TRP subfamily C member (TRPC) 1, TRPC3, TRPC4 and TRPC6 have been found in neutrophils (Brechard et al., 2008; Heiner et al., 2003b; Itagaki et al., 2004; McMeekin et al., 2006), along with TRP channel subfamily M member 2 (TRPM2) and TRP vanilloid 1 [TRPV1; Heiner et al., 2003a]. However, two new proteins, STIM1 (an ER Ca2+ sensor) and Orai1 (a Ca2+ channel), have recently been proposed as the missing links in the SOCE mechanisms (Fig. 1) (Smyth et al., 2006; Taylor, 2006). In spite of this, there is some conflicting evidence on the role and the molecular basis of SOCE in neutrophils.
Neutrophils are the first line of defense against pathogens in bovines; however, they are also one of the most aggressive cells during the inflammatory process, causing injury in surrounding tissues. At present, anti-inflammatory drugs are limited in acute diseases, such as pneumonia, mastitis and endometritis, because neutrophils are mostly insensitive. One of the earliest events during neutrophil activation is the increase in intracellular calcium concentration. The calcium movement is attributed to the release from intracellular stores and influx through the calcium channels in the plasma membrane, a process called store operated calcium entry (SOCE). Recently, several calcium influx blockers have been shown to have strong effects on bovine neutrophils, and this suggests that the manipulation of this pathway can be useful in the control of neutrophil functions during acute inflammatory processes. In this paper, we will review the role of calcium influx as a potential anti-inflammatory target and summarize the most recent evidences for this in bovine neutrophils.

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Trends in Biochemical Sciences

UpdateResearch FocusStore-operated Ca2+ entry: a STIMulating stOrai

Section snippets

The birth of store-operated Ca2+ entry

STIM1 is the Ca2+ sensor

Orai proteins form the missing channel

How do the players play?

Not the last word

Acknowledgements

Glossary

Biochim. Biophys. Acta

Trends Biochem. Sci.

Cell Calcium

Curr. Biol.

J. Biol. Chem.

J. Biol. Chem.

Biochim. Biophys. Acta

Biochim. Biophys. Acta

J. Biol. Chem.

Trends Cell Biol.

Cell

Release of Ca2+ from a nonmitochondrial store of pancreatic acinar cells by inositol-1,4,5-trisphosphate

Nature

Exchange characteristics of the noradrenaline-sensitive calcium store in vascular smooth muscle cells of rabbit ear artery

J. Physiol.

Store-operated calcium channels

Physiol. Rev.

Update
Research Focus
Store-operated Ca²⁺ entry: a STIMulating stOrai

The birth of store-operated Ca²⁺ entry

STIM1 is the Ca²⁺ sensor

Release of Ca²⁺ from a nonmitochondrial store of pancreatic acinar cells by inositol-1,4,5-trisphosphate