Abstract
Calcium acts as a second messenger in many cell types, including lymphocytes. Resting lymphocytes maintain a low concentration of Ca2+. However, engagement of antigen receptors induces calcium influx from the extracellular space by several routes. A chief mechanism of Ca2+ entry in lymphocytes is through store-operated calcium (SOC) channels. The identification of two important molecular components of SOC channels, CRACM1 (the pore-forming subunit) and STIM1 (the sensor of stored calcium), has allowed genetic and molecular manipulation of the SOC entry pathway. In this review, we highlight advances in the understanding of Ca2+ signaling in lymphocytes with special emphasis on SOC entry. We also discuss outstanding questions and probable future directions of the field.
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16 January 2009
NOTE: In the version of this article initially published, the published online date is 17 January 2009 and the ovals indicating store-dependent channels in the bottom row of Figure 2 are blue. The published online date should be 17 December 2008 and the ovals should be black . The errors have been corrected in the HTML and PDF versions of the article.
References
Parekh, A.B. & Putney, J.W., Jr. Store-operated calcium channels. Physiol. Rev. 85, 757–810 (2005).
Liou, J. et al. STIM is a Ca2+ sensor essential for Ca2+-store-depletion-triggered Ca2+ influx. Curr. Biol. 15, 1235–1241 (2005).
Zhang, S.L. et al. STIM1 is a Ca2+ sensor that activates CRAC channels and migrates from the Ca2+ store to the plasma membrane. Nature 437, 902–905 (2005).
Vig, M. et al. CRACM1 is a plasma membrane protein essential for store-operated Ca2+ entry. Science 312, 1220–1223 (2006).
Feske, S. et al. A mutation in Orai1 causes immune deficiency by abrogating CRAC channel function. Nature 441, 179–185 (2006).
Zhang, S.L. et al. Genome-wide RNAi screen of Ca2+ influx identifies genes that regulate Ca2+ release-activated Ca2+ channel activity. Proc. Natl. Acad. Sci. USA 103, 9357–9362 (2006).
Philipp, S. et al. TRPC3 mediates T-cell receptor-dependent calcium entry in human T-lymphocytes. J. Biol. Chem. 278, 26629–26638 (2003).
Venkatachalam, K., Ma, H.T., Ford, D.L. & Gill, D.L. Expression of functional receptor-coupled TRPC3 channels in DT40 triple receptor InsP3 knockout cells. J. Biol. Chem. 276, 33980–33985 (2001).
Putney, J.W., Jr. Capacitative calcium entry: sensing the calcium stores. J. Cell Biol. 169, 381–382 (2005).
Yuan, J.P., Zeng, W., Huang, G.N., Worley, P.F. & Muallem, S. STIM1 heteromultimerizes TRPC channels to determine their function as store-operated channels. Nat. Cell Biol. 9, 636–645 (2007).
Villereal, M.L. Mechanism and functional significance of TRPC channel multimerization. Semin. Cell Dev. Biol. 17, 618–629 (2006).
Hardie, R.C. TRP channels and lipids: from Drosophila to mammalian physiology. J. Physiol. 578, 9–24 (2007).
Rao, G.K. & Kaminski, N.E. Induction of intracellular calcium elevation by Delta9-tetrahydrocannabinol in T cells involves TRPC1 channels. J. Leukoc. Biol. 79, 202–213 (2006).
Lioudyno, M.I. et al. Orai1 and STIM1 move to the immunological synapse and are up-regulated during T cell activation. Proc. Natl. Acad. Sci. USA 105, 2011–2016 (2008).
Malek, T.R. The biology of interleukin-2. Annu. Rev. Immunol. 26, 453–479 (2008).
Baba, Y. et al. Essential function for the calcium sensor STIM1 in mast cell activation and anaphylactic responses. Nat. Immunol. 9, 81–88 (2008).
Dolmetsch, R.E., Lewis, R.S., Goodnow, C.C. & Healy, J.I. Differential activation of transcription factors induced by Ca2+ response amplitude and duration. Nature 386, 855–858 (1997).
Ho, N., Gullberg, M. & Chatila, T. Activation protein 1-dependent transcriptional activation of interleukin 2 gene by Ca2+/calmodulin kinase type IV/Gr. J. Exp. Med. 184, 101–112 (1996).
Crabtree, G.R. & Olson, E.N. NFAT signaling: choreographing the social lives of cells. Cell 109, S67–S79 (2002).
Huang, G.N. et al. NFAT binding and regulation of T cell activation by the cytoplasmic scaffolding Homer proteins. Science 319, 476–481 (2008).
Stathopulos, P.B., Li, G.Y., Plevin, M.J., Ames, J.B. & Ikura, M. Stored Ca2+ depletion-induced oligomerization of stromal interaction molecule 1 (STIM1) via the EF-SAM region: an initiation mechanism for capacitive Ca2+ entry. J. Biol. Chem. 281, 35855–35862 (2006).
Liou, J., Fivaz, M., Inoue, T. & Meyer, T. Live-cell imaging reveals sequential oligomerization and local plasma membrane targeting of stromal interaction molecule 1 after Ca2+ store depletion. Proc. Natl. Acad. Sci. USA 104, 9301–9306 (2007).
Stathopulos, P.B., Zheng, L., Li, G.Y., Plevin, M.J. & Ikura, M. Structural and mechanistic insights into STIM1-mediated initiation of store-operated calcium entry. Cell 135, 110–122 (2008).
Luik, R.M., Wu, M.M., Buchanan, J. & Lewis, R.S. The elementary unit of store-operated Ca2+ entry: local activation of CRAC channels by STIM1 at ER-plasma membrane junctions. J. Cell Biol. 174, 815–825 (2006).
Luik, R.M., Wang, B., Prakriya, M., Wu, M.M. & Lewis, R.S. Oligomerization of STIM1 couples ER calcium depletion to CRAC channel activation. Nature 454, 538–542 (2008).
Baba, Y. et al. Coupling of STIM1 to store-operated Ca2+ entry through its constitutive and inducible movement in the endoplasmic reticulum. Proc. Natl. Acad. Sci. USA 103, 16704–16709 (2006).
Soboloff, J. et al. STIM2 is an inhibitor of STIM1-mediated store-operated Ca2+ entry. Curr. Biol. 16, 1465–1470 (2006).
Brandman, O., Liou, J., Park, W.S. & Meyer, T. STIM2 is a feedback regulator that stabilizes basal cytosolic and endoplasmic reticulum Ca2+ levels. Cell 131, 1327–1339 (2007).
Oh-Hora, M. et al. Dual functions for the endoplasmic reticulum calcium sensors STIM1 and STIM2 in T cell activation and tolerance. Nat. Immunol. 9, 432–443 (2008).
Peinelt, C. et al. Amplification of CRAC current by STIM1 and CRACM1 (Orai1). Nat. Cell Biol. 8, 771–773 (2006).
Mercer, J.C. et al. Large store-operated calcium selective currents due to co-expression of Orai1 or Orai2 with the intracellular calcium sensor, Stim1. J. Biol. Chem. 281, 24979–24990 (2006).
Soboloff, J. et al. Orai1 and STIM reconstitute store-operated calcium channel function. J. Biol. Chem. 281, 20661–20665 (2006).
Vig, M. et al. CRACM1 multimers form the ion-selective pore of the CRAC channel. Curr. Biol. 16, 2073–2079 (2006).
Yeromin, A.V. et al. Molecular identification of the CRAC channel by altered ion selectivity in a mutant of Orai. Nature 443, 226–229 (2006).
Prakriya, M. et al. Orai1 is an essential pore subunit of the CRAC channel. Nature 443, 230–233 (2006).
Lis, A. et al. CRACM1, CRACM2, and CRACM3 are store-operated Ca2+ channels with distinct functional properties. Curr. Biol. 17, 794–800 (2007).
Ong, H.L. et al. Dynamic assembly of TRPC1-STIM1-Orai1 ternary complex is involved in store-operated calcium influx. Evidence for similarities in store-operated and calcium release-activated calcium channel components. J. Biol. Chem. 282, 9105–9116 (2007).
Mignen, O., Thompson, J.L. & Shuttleworth, T.J. Orai1 subunit stoichiometry of the mammalian CRAC channel pore. J. Physiol. 586, 419–425 (2008).
Ji, W. et al. Functional stoichiometry of the unitary calcium-release-activated calcium channel. Proc. Natl. Acad. Sci. USA 105, 13668–13673 (2008).
Wu, M.M., Buchanan, J., Luik, R.M. & Lewis, R.S. Ca2+ store depletion causes STIM1 to accumulate in ER regions closely associated with the plasma membrane. J. Cell Biol. 174, 803–813 (2006).
Huang, G.N. et al. STIM1 carboxyl-terminus activates native SOC, Icrac and TRPC1 channels. Nat. Cell Biol. 8, 1003–1010 (2006).
Barr, V.A. et al. Dynamic movement of the calcium sensor STIM1 and the calcium channel Orai1 in activated T-cells: puncta and distal caps. Mol. Biol. Cell 19, 2802–2817 (2008).
Muik, M. et al. Dynamic coupling of the putative coiled-coil domain of ORAI1 with STIM1 mediates ORAI1 channel activation. J. Biol. Chem. 283, 8014–8022 (2008).
Gwack, Y. et al. Biochemical and functional characterization of Orai proteins. J. Biol. Chem. 282, 16232–16243 (2007).
Varnai, P., Toth, B., Toth, D.J., Hunyady, L. & Balla, T. Visualization and manipulation of plasma membrane-endoplasmic reticulum contact sites indicates the presence of additional molecular components within the STIM1-Orai1 complex. J. Biol. Chem. 282, 29678–29690 (2007).
Smani, T. et al. A novel mechanism for the store-operated calcium influx pathway. Nat. Cell Biol. 6, 113–120 (2004).
Li, Z. et al. Mapping the interacting domains of STIM1 and Orai1 in Ca2+ release-activated Ca2+ channel activation. J. Biol. Chem. 282, 29448–29456 (2007).
Penna, A. et al. The CRAC channel consists of a tetramer formed by STIM-induced dimerization of Orai dimers. Nature 456, 116–120 (2008).
Leslie, M. Mast cells show their might. Science 317, 614–616 (2007).
Nadler, M.J. & Kinet, J.P. Uncovering new complexities in mast cell signaling. Nat. Immunol. 3, 707–708 (2002).
Vig, M. et al. Defective mast cell effector functions in mice lacking the CRACM1 pore subunit of store-operated calcium release–activated calcium channels. Nat. Immunol. 9, 89–96 (2008).
Launay, P. et al. TRPM4 is a Ca2+-activated nonselective cation channel mediating cell membrane depolarization. Cell 109, 397–407 (2002).
Launay, P. et al. TRPM4 regulates calcium oscillations after T cell activation. Science 306, 1374–1377 (2004).
Vennekens, R. et al. Increased IgE-dependent mast cell activation and anaphylactic responses in mice lacking the calcium-activated nonselective cation channel TRPM4. Nat. Immunol. 8, 312–320 (2007).
Chang, W.C. et al. Local Ca2+ influx through Ca2+ release-activated Ca2+ (CRAC) channels stimulates production of an intracellular messenger and an intercellular pro-inflammatory signal. J. Biol. Chem. 283, 4622–4631 (2008).
Rettig, J. & Neher, E. Emerging roles of presynaptic proteins in Ca++-triggered exocytosis. Science 298, 781–785 (2002).
Kalesnikoff, J. et al. SHIP negatively regulates IgE + antigen-induced IL-6 production in mast cells by inhibiting NF-κB activity. J. Immunol. 168, 4737–4746 (2002).
Jenkins, M.K., Schwartz, R.H. & Pardoll, D.M. Effects of cyclosporine A on T cell development and clonal deletion. Science 241, 1655–1658 (1988).
Gao, E.K., Lo, D., Cheney, R., Kanagawa, O. & Sprent, J. Abnormal differentiation of thymocytes in mice treated with cyclosporin A. Nature 336, 176–179 (1988).
Bueno, O.F., Brandt, E.B., Rothenberg, M.E. & Molkentin, J.D. Defective T cell development and function in calcineurin A β-deficient mice. Proc. Natl. Acad. Sci. USA 99, 9398–9403 (2002).
Neilson, J.R., Winslow, M.M., Hur, E.M. & Crabtree, G.R. Calcineurin B1 is essential for positive but not negative selection during thymocyte development. Immunity 20, 255–266 (2004).
Oukka, M. et al. The transcription factor NFAT4 is involved in the generation and survival of T cells. Immunity 9, 295–304 (1998).
Gwack, Y. et al. Hair loss and defective T and B cell function in mice lacking ORAI1. Mol. Cell Biol. (2008).
DeHaven, W.I., Smyth, J.T., Boyles, R.R. & Putney, J.W., Jr. Calcium inhibition and calcium potentiation of Orai1, Orai2, and Orai3 calcium release-activated calcium channels. J. Biol. Chem. 282, 17548–17556 (2007).
Jin, J. et al. Deletion of Trpm7 disrupts embryonic development and thymopoiesis without altering Mg2+ homeostasis. Science 322, 756–760 (2008).
Lewis, R.S. & Cahalan, M.D. Mitogen-induced oscillations of cytosolic Ca2+ and transmembrane Ca2+ current in human leukemic T cells. Cell Regul. 1, 99–112 (1989).
Zweifach, A. & Lewis, R.S. Mitogen-regulated Ca2+ current of T lymphocytes is activated by depletion of intracellular Ca2+ stores. Proc. Natl. Acad. Sci. USA 90, 6295–6299 (1993).
Partiseti, M. et al. The calcium current activated by T cell receptor and store depletion in human lymphocytes is absent in a primary immunodeficiency. J. Biol. Chem. 269, 32327–32335 (1994).
Feske, S. et al. Severe combined immunodeficiency due to defective binding of the nuclear factor of activated T cells in T lymphocytes of two male siblings. Eur. J. Immunol. 26, 2119–2126 (1996).
Peng, S.L., Gerth, A.J., Ranger, A.M. & Glimcher, L.H. NFATc1 and NFATc2 together control both T and B cell activation and differentiation. Immunity 14, 13–20 (2001).
Kotturi, M.F., Hunt, S.V. & Jefferies, W.A. Roles of CRAC and Cav-like channels in T cells: more than one gatekeeper? Trends Pharmacol. Sci. 27, 360–367 (2006).
Badou, A. et al. Critical role for the β regulatory subunits of Cav channels in T lymphocyte function. Proc. Natl. Acad. Sci. USA 103, 15529–15534 (2006).
Gomez-Ospina, N., Tsuruta, F., Barreto-Chang, O., Hu, L. & Dolmetsch, R. The C terminus of the L-type voltage-gated calcium channel Cav1.2 encodes a transcription factor. Cell 127, 591–606 (2006).
Gouy, H., Cefai, D., Christensen, S.B., Debre, P. & Bismuth, G. Ca2+ influx in human T lymphocytes is induced independently of inositol phosphate production by mobilization of intracellular Ca2+ stores. A study with the Ca2+ endoplasmic reticulum-ATPase inhibitor thapsigargin. Eur. J. Immunol. 20, 2269–2275 (1990).
Telford, W.G. & Miller, R.A. Detection of plasma membrane Ca2+-ATPase activity in mouse T lymphocytes by flow cytometry using fluo-3-loaded vesicles. Cytometry 24, 243–250 (1996).
Bautista, D.M., Hoth, M. & Lewis, R.S. Enhancement of calcium signalling dynamics and stability by delayed modulation of the plasma-membrane calcium-ATPase in human T cells. J. Physiol. (Lond.) 541, 877–894 (2002).
Jayaraman, T., Ondriasova, E., Ondrias, K., Harnick, D.J. & Marks, A.R. The inositol 1,4,5-trisphosphate receptor is essential for T-cell receptor signaling. Proc. Natl. Acad. Sci. USA 92, 6007–6011 (1995).
Guse, A.H. et al. Regulation of calcium signalling in T lymphocytes by the second messenger cyclic ADP-ribose. Nature 398, 70–73 (1999).
Sei, Y., Gallagher, K.L. & Basile, A.S. Skeletal muscle type ryanodine receptor is involved in calcium signaling in human B lymphocytes. J. Biol. Chem. 274, 5995–6002 (1999).
Guerini, D., Coletto, L. & Carafoli, E. Exporting calcium from cells. Cell Calcium 38, 281–289 (2005).
Balasubramanyam, M., Rohowsky-Kochan, C., Reeves, J.P. & Gardner, J.P. Na+/Ca2+ exchange-mediated calcium entry in human lymphocytes. J. Clin. Invest. 94, 2002–2008 (1994).
Saris, N.E. & Carafoli, E. A historical review of cellular calcium handling, with emphasis on mitochondria. Biochemistry (Mosc.) 70, 187–194 (2005).
Hoth, M., Fanger, C.M. & Lewis, R.S. Mitochondrial regulation of store-operated calcium signaling in T lymphocytes. J. Cell Biol. 137, 633–648 (1997).
Beeton, C. & Chandy, K.G. Potassium channels, memory T cells, and multiple sclerosis. Neuroscientist 11, 550–562 (2005).
Cowen, D.S. et al. Extracellular adenosine triphosphate activates calcium mobilization in human phagocytic leukocytes and neutrophil/monocyte progenitor cells. J. Clin. Invest. 83, 1651–1660 (1989).
Cui, J., Bian, J.S., Kagan, A. & McDonald, T.V. CaT1 contributes to the stores-operated calcium current in Jurkat T-lymphocytes. J. Biol. Chem. 277, 47175–47183 (2002).
Perraud, A.L. et al. ADP-ribose gating of the calcium-permeable LTRPC2 channel revealed by Nudix motif homology. Nature 411, 595–599 (2001).
Sano, Y. et al. Immunocyte Ca2+ influx system mediated by LTRPC2. Science 293, 1327–1330 (2001).
Nadler, M.J. et al. LTRPC7 is a Mg.ATP-regulated divalent cation channel required for cell viability. Nature 411, 590–595 (2001).
Prakriya, M. & Lewis, R.S. Separation and characterization of currents through store-operated CRAC channels and Mg2+-inhibited cation (MIC) channels. J. Gen. Physiol. 119, 487–507 (2002).
Shuttleworth, T.J. What drives calcium entry during [Ca2+]i oscillations?–challenging the capacitative model. Cell Calcium 25, 237–246 (1999).
Dellis, O. et al. Ca2+ entry through plasma membrane IP3 receptors. Science 313, 229–233 (2006).
Acknowledgements
We thank P. Rao and D. Okuhara for discussions and J.W. Putney for critical reading of this manuscript, and we apologize to those colleagues whose work we could not cite because of space limitations. Supported by the Cancer Research Institute–Irvington Institute Fellowship Program (M.V.) and the US National Institutes of Health (GM 053950 to J.-P.K.).
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M.V. & J.-P.K. are consultants for Synta Pharmaceuticals.
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Vig, M., Kinet, JP. Calcium signaling in immune cells. Nat Immunol 10, 21–27 (2009). https://doi.org/10.1038/ni.f.220
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DOI: https://doi.org/10.1038/ni.f.220
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