Molecular Basis of Calcium Signaling in Lymphocytes: STIM and ORAI

Overview

Journal Annu Rev Immunol

Specialty Allergy & Immunology

Date 2010 Mar 24

PMID 20307213

Citations 420

Authors

Patrick G Hogan

Richard S Lewis

Anjana Rao

Affiliations

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Abstract

Ca(2+) entry into cells of the peripheral immune system occurs through highly Ca(2+)-selective channels known as CRAC (calcium release-activated calcium) channels. CRAC channels are a very well-characterized example of store-operated Ca(2+) channels, so designated because they open when the endoplasmic reticulum (ER) Ca(2+) store becomes depleted. Physiologically, Ca(2+) is released from the ER lumen into the cytoplasm when activated receptors couple to phospholipase C and trigger production of the second messenger inositol 1,4,5-trisphosphate (IP(3)). IP(3) binds to IP(3) receptors in the ER membrane and activates Ca(2+) release. The proteins STIM and ORAI were discovered through limited and genome-wide RNAi screens, respectively, performed in Drosophila cells and focused on identifying modulators of store-operated Ca(2+) entry. STIM1 and STIM2 sense the depletion of ER Ca(2+) stores, whereas ORAI1 is a pore subunit of the CRAC channel. In this review, we discuss selected aspects of Ca(2+) signaling in cells of the immune system, focusing on the roles of STIM and ORAI proteins in store-operated Ca(2+) entry.

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References

Hogan P, Chen L, Nardone J, Rao A . Transcriptional regulation by calcium, calcineurin, and NFAT. Genes Dev. 2003; 17(18):2205-32. DOI: 10.1101/gad.1102703. View

Skokos D, Shakhar G, Varma R, Waite J, Cameron T, Lindquist R . Peptide-MHC potency governs dynamic interactions between T cells and dendritic cells in lymph nodes. Nat Immunol. 2007; 8(8):835-44. DOI: 10.1038/ni1490. View

Gwack Y, Srikanth S, Oh-Hora M, Hogan P, Lamperti E, Yamashita M . Hair loss and defective T- and B-cell function in mice lacking ORAI1. Mol Cell Biol. 2008; 28(17):5209-22. PMC: 2519726. DOI: 10.1128/MCB.00360-08. View

Kotturi M, Hunt S, Jefferies W . Roles of CRAC and Cav-like channels in T cells: more than one gatekeeper?. Trends Pharmacol Sci. 2006; 27(7):360-7. DOI: 10.1016/j.tips.2006.05.007. View

Bolotina V, Csutora P . CIF and other mysteries of the store-operated Ca2+-entry pathway. Trends Biochem Sci. 2005; 30(7):378-87. DOI: 10.1016/j.tibs.2005.05.009. View

Philipp S, Strauss B, Hirnet D, Wissenbach U, Mery L, Flockerzi V . TRPC3 mediates T-cell receptor-dependent calcium entry in human T-lymphocytes. J Biol Chem. 2003; 278(29):26629-38. DOI: 10.1074/jbc.M304044200. View

Huang Y, Zhou Y, Wong H, Chen Y, Chen Y, Wang S . A single EF-hand isolated from STIM1 forms dimer in the absence and presence of Ca2+. FEBS J. 2009; 276(19):5589-97. PMC: 2866080. DOI: 10.1111/j.1742-4658.2009.07240.x. View

Li Z, Lu J, Xu P, Xie X, Chen L, Xu T . Mapping the interacting domains of STIM1 and Orai1 in Ca2+ release-activated Ca2+ channel activation. J Biol Chem. 2007; 282(40):29448-56. DOI: 10.1074/jbc.M703573200. View

Stathopulos P, Zheng L, Li G, Plevin M, Ikura M . Structural and mechanistic insights into STIM1-mediated initiation of store-operated calcium entry. Cell. 2008; 135(1):110-22. DOI: 10.1016/j.cell.2008.08.006. View

10.

Parekh A, Putney Jr J . Store-operated calcium channels. Physiol Rev. 2005; 85(2):757-810. DOI: 10.1152/physrev.00057.2003. View

11.

Honnappa S, Montenegro Gouveia S, Weisbrich A, Damberger F, Bhavesh N, Jawhari H . An EB1-binding motif acts as a microtubule tip localization signal. Cell. 2009; 138(2):366-76. DOI: 10.1016/j.cell.2009.04.065. View

12.

Yue L, Peng J, Hediger M, Clapham D . CaT1 manifests the pore properties of the calcium-release-activated calcium channel. Nature. 2001; 410(6829):705-9. DOI: 10.1038/35070596. View

13.

Dolmetsch R, Xu K, Lewis R . Calcium oscillations increase the efficiency and specificity of gene expression. Nature. 1998; 392(6679):933-6. DOI: 10.1038/31960. View

14.

Takeshima H, Komazaki S, Nishi M, Iino M, Kangawa K . Junctophilins: a novel family of junctional membrane complex proteins. Mol Cell. 2000; 6(1):11-22. DOI: 10.1016/s1097-2765(00)00003-4. View

15.

Feske S, Prakriya M, Rao A, Lewis R . A severe defect in CRAC Ca2+ channel activation and altered K+ channel gating in T cells from immunodeficient patients. J Exp Med. 2005; 202(5):651-62. PMC: 2212870. DOI: 10.1084/jem.20050687. View

16.

Ji W, Xu P, Li Z, Lu J, Liu L, Zhan Y . Functional stoichiometry of the unitary calcium-release-activated calcium channel. Proc Natl Acad Sci U S A. 2008; 105(36):13668-73. PMC: 2533247. DOI: 10.1073/pnas.0806499105. View

17.

Ren Y, Pan F, Parvez S, Fleig A, Chong C, Xu J . Clofazimine inhibits human Kv1.3 potassium channel by perturbing calcium oscillation in T lymphocytes. PLoS One. 2008; 3(12):e4009. PMC: 2602975. DOI: 10.1371/journal.pone.0004009. View

18.

Yeromin A, Zhang S, Jiang W, Yu Y, Safrina O, Cahalan M . Molecular identification of the CRAC channel by altered ion selectivity in a mutant of Orai. Nature. 2006; 443(7108):226-9. PMC: 2756048. DOI: 10.1038/nature05108. View

19.

Wulff H, Beeton C, Chandy K . Potassium channels as therapeutic targets for autoimmune disorders. Curr Opin Drug Discov Devel. 2003; 6(5):640-7. View

20.

Heuser J, Salpeter S . Organization of acetylcholine receptors in quick-frozen, deep-etched, and rotary-replicated Torpedo postsynaptic membrane. J Cell Biol. 1979; 82(1):150-73. PMC: 2110412. DOI: 10.1083/jcb.82.1.150. View