Cardiovascular and Hemostatic Disorders: SOCE and Ca2+ Handling in Platelet Dysfunction

  • Jose J. Lopez
  • Gines M. Salido
  • Juan A. RosadoEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 993)


Among the Ca2+ entry mechanisms in platelets, store-operated Ca2+ entry (SOCE) plays a prominent role as it is necessary to achieve full activation of platelet functions and replenish intracellular Ca2+ stores. In platelets, as in other non-excitable cells, SOCE has been reported to involve the activation of plasma membrane channels by the ER Ca2+ sensor STIM1. Despite electrophysiological studies are not possible in human platelets, indirect analyses have revealed that the Ca2+-permeable channels involve Orai1 and, most likely, TRPC1 subunits. A relevant role for the latter has not been found in mouse platelets. There is a body of evidence revealing a number of abnormalities in SOCE or in its molecular regulators that result in qualitative platelet disorders and, as a consequence, altered platelet responsiveness upon stimulation with multiple physiological agonists. Platelet SOCE abnormalities include STIM1 and Orai1 mutations. This chapter summarizes the current knowledge in this field, as well as the disorders associated to platelet SOCE dysfunction.


Platelets STIM1 STIM2 Orai1 TRPC1 SARAF Homer1 



This work was supported by MINECO (Grants BFU2013-45564-C2-1-P and BFU2016-74932-C2-1-P) and Junta de Extremadura-FEDER (GR15029).


  1. Adam F, Khatib AM, Lopez JJ, Vatier C, Turpin S, Muscat A, Soulet F, Aries A, Jardin I, Bobe R, Stepanian A, de Prost D, Dray C, Rosado JA, Valet P, Feve B, Siegfried G (2016) Apelin: an antithrombotic factor that inhibits platelet function. Blood 127:908–920PubMedCrossRefGoogle Scholar
  2. Ahmad F, Boulaftali Y, Greene TK, Ouellette TD, Poncz M, Feske S, Bergmeier W (2011) Relative contributions of stromal interaction molecule 1 and CalDAG-GEFI to calcium-dependent platelet activation and thrombosis. J Thromb Haemost 9:2077–2086PubMedPubMedCentralCrossRefGoogle Scholar
  3. Albarran L, Berna-Erro A, Dionisio N, Redondo PC, Lopez E, Lopez JJ, Salido GM, Brull Sabate JM, Rosado JA (2014) TRPC6 participates in the regulation of cytosolic basal calcium concentration in murine resting platelets. Biochim Biophys Acta 1843:789–796PubMedCrossRefGoogle Scholar
  4. Albarran L, Lopez JJ, Amor NB, Martin-Cano FE, Berna-Erro A, Smani T, Salido GM, Rosado JA (2016a) Dynamic interaction of SARAF with STIM1 and Orai1 to modulate store-operated calcium entry. Sci Rep 6:24452PubMedPubMedCentralCrossRefGoogle Scholar
  5. Albarran L, Lopez JJ, Gomez LJ, Salido GM, Rosado JA (2016b) SARAF modulates TRPC1, but not TRPC6, channel function in a STIM1-independent manner. Biochem J 473:3581–3595PubMedCrossRefGoogle Scholar
  6. Albarran L, Lopez JJ, Woodard GE, Salido GM, Rosado JA (2016c) Store-operated Ca2+ entry-associated regulatory factor (SARAF) plays an important role in the regulation of Arachidonate-regulated Ca2+ (ARC) channels. J Biol Chem 291:6982–6988PubMedPubMedCentralCrossRefGoogle Scholar
  7. Albarran L, Regodon S, Salido GM, Lopez JJ, Rosado JA (2016d) Role of STIM1 in the surface expression of SARAF. Channels 11:84–88PubMedPubMedCentralCrossRefGoogle Scholar
  8. Ambudkar I, de Souza LB, Ong HL (2017) TRPC1, Orai1, and STIM1 in SOCE: friends in tight spaces. Cell Calcium. doi: 10.1016/j.ceca.2016.12.009
  9. Bakowski D, Parekh AB (2002) Monovalent cation permeability and Ca(2+) block of the store-operated Ca(2+) current I(CRAC )in rat basophilic leukemia cells. Pflugers Arch 443:892–902PubMedCrossRefGoogle Scholar
  10. Ben Amor NB, Zbidi H, Bouaziz A, Jardin I, Hernandez-Cruz JM, Salido GM, Rosado JA, Bartegi A (2009) Acidic-store depletion is required for human platelet aggregation. Blood Coagul Fibrinolysis 20:511–516CrossRefGoogle Scholar
  11. Berg LP, Shamsher MK, El-Daher SS, Kakkar VV, Authi KS (1997) Expression of human TRPC genes in the megakaryocytic cell lines MEG01, DAMI and HEL. FEBS Lett 403:83–86PubMedCrossRefGoogle Scholar
  12. Bergmeier W, Oh-Hora M, McCarl CA, Roden RC, Bray PF, Feske S (2009) R93W mutation in Orai1 causes impaired calcium influx in platelets. Blood 113:675–678PubMedPubMedCentralCrossRefGoogle Scholar
  13. Bergmeier W, Weidinger C, Zee I, Feske S (2013) Emerging roles of store-operated Ca(2+) entry through STIM and ORAI proteins in immunity, hemostasis and cancer. Channels (Austin) 7:379–391CrossRefGoogle Scholar
  14. Berna-Erro A, Galan C, Dionisio N, Gomez LJ, Salido GM, Rosado JA (2012) Capacitative and non-capacitative signaling complexes in human platelets. Biochim Biophys Acta 1823:1242–1251PubMedCrossRefGoogle Scholar
  15. Berna-Erro A, Jardin I, Smani T, Rosado JA (2016) Regulation of platelet function by Orai, STIM and TRP. Adv Exp Med Biol 898:157–181PubMedCrossRefGoogle Scholar
  16. Bizzonero J (1882) Über einen formbestandtheil des blutes und dessen rolle bei der thrombose und der blutgerinnung. Virchows Arch Pathol Anat Physiol Klin Med 90:261–332CrossRefGoogle Scholar
  17. Bobe R, Bredoux R, Wuytack F, Quarck R, Kovacs T, Papp B, Corvazier E, Magnier C, Enouf J (1994) The rat platelet 97-kDa Ca2+ATPase isoform is the sarcoendoplasmic reticulum Ca2+ATPase 3 protein. J Biol Chem 269:1417–1424PubMedGoogle Scholar
  18. Bohm J, Chevessier F, Maues De Paula A, Koch C, Attarian S, Feger C, Hantai D, Laforet P, Ghorab K, Vallat JM, Fardeau M, Figarella-Branger D, Pouget J, Romero NB, Koch M, Ebel C, Levy N, Krahn M, Eymard B, Bartoli M, Laporte J (2013) Constitutive activation of the calcium sensor STIM1 causes tubular-aggregate myopathy. Am J Hum Genet 92:271–278PubMedPubMedCentralCrossRefGoogle Scholar
  19. Borst O, Münzer P, Schmid E, Schmidt EM, Russo A, Walker B, Yang W, Leibrock C, Szteyn K, Schmidt S, Elvers M, Faggio C, Shumilina E, Kuro-o M, Gawaz M, Lang F (2014) 1,25(OH)2 vitamin D3-dependent inhibition of platelet Ca2+ signaling and thrombus formation in klotho-deficient mice. FASEB J 28:2108–2119PubMedCrossRefGoogle Scholar
  20. Braun A, Varga-Szabo D, Kleinschnitz C, Pleines I, Bender M, Austinat M, Bosl M, Stoll G, Nieswandt B (2009) Orai1 (CRACM1) is the platelet SOC channel and essential for pathological thrombus formation. Blood 113:2056–2063PubMedCrossRefGoogle Scholar
  21. Cao E, Liao M, Cheng Y, Julius D (2013) TRPV1 structures in distinct conformations reveal activation mechanisms. Nature 504:113–118PubMedPubMedCentralCrossRefGoogle Scholar
  22. Cavallini L, Coassin M, Alexandre A (1995) Two classes of agonist-sensitive Ca2+ stores in platelets, as identified by their differential sensitivity to 2,5-di-(tert-butyl)-1,4-benzohydroquinone and thapsigargin. Biochem J 310(Pt 2):449–452PubMedPubMedCentralCrossRefGoogle Scholar
  23. Cui B, Yang X, Li S, Lin Z, Wang Z, Dong C, Shen Y (2013) The inhibitory helix controls the intramolecular conformational switching of the C-terminus of STIM1. PLoS One 8:e74735PubMedPubMedCentralCrossRefGoogle Scholar
  24. Dell’Angelica EC, Mullins C, Caplan S (2000) Lysosome-related organelles. FASEB J 14:1265–1278PubMedCrossRefGoogle Scholar
  25. Derler I, Fahrner M, Muik M, Lackner B, Schindl R, Groschner K, Romanin C (2009) A Ca2+ release-activated Ca2+ (CRAC) modulatory domain (CMD) within STIM1 mediates fast Ca2+-dependent inactivation of ORAI1 channels. J Biol Chem 284:24933–24938PubMedPubMedCentralCrossRefGoogle Scholar
  26. Derler I, Plenk P, Fahrner M, Muik M, Jardin I, Schindl R, Gruber HJ, Groschner K, Romanin C (2013) The extended transmembrane Orai1 N-terminal (ETON) region combines binding interface and gate for Orai1 activation by STIM1. J Biol Chem 288:29025–29034PubMedPubMedCentralCrossRefGoogle Scholar
  27. Desai PN, Zhang X, Wu S, Janoshazi A, Bolimuntha S, Putney JW, Trebak M (2015) Multiple types of calcium channels arising from alternative translation initiation of the Orai1 message. Sci Signal 8:ra74PubMedPubMedCentralCrossRefGoogle Scholar
  28. Dionisio N, Albarran L, Berna-Erro A, Hernandez-Cruz JM, Salido GM, Rosado JA (2011) Functional role of the calmodulin- and inositol 1,4,5-trisphosphate receptor-binding (CIRB) site of TRPC6 in human platelet activation. Cell Signal 23:1850–1856PubMedCrossRefGoogle Scholar
  29. Ebbeling L, Robertson C, McNicol A, Gerrard JM (1992) Rapid ultrastructural changes in the dense tubular system following platelet activation. Blood 80:718–723PubMedGoogle Scholar
  30. Fahrner M, Derler I, Jardin I, Romanin C (2013) The STIM1/Orai signaling machinery. Channels (Austin) 7:330–343CrossRefGoogle Scholar
  31. Fahrner M, Muik M, Schindl R, Butorac C, Stathopulos P, Zheng L, Jardin I, Ikura M, Romanin C (2014) A coiled-coil clamp controls both conformation and clustering of stromal interaction molecule 1 (STIM1). J Biol Chem 289:33231–33244PubMedPubMedCentralCrossRefGoogle Scholar
  32. Fasolato C, Nilius B (1998) Store depletion triggers the calcium release-activated calcium current (ICRAC) in macrovascular endothelial cells: a comparison with Jurkat and embryonic kidney cell lines. Pflugers Arch 436:69–74PubMedCrossRefGoogle Scholar
  33. Feske S (2010) CRAC channelopathies. Pflugers Arch 460:417–435PubMedPubMedCentralCrossRefGoogle Scholar
  34. Feske S, Prakriya M (2013) Conformational dynamics of STIM1 activation. Nat Struct Mol Biol 20:918–919PubMedPubMedCentralCrossRefGoogle Scholar
  35. Feske S, Prakriya M, Rao A, Lewis RS (2005) A severe defect in CRAC Ca2+ channel activation and altered K+ channel gating in T cells from immunodeficient patients. J Exp Med 202:651–662PubMedPubMedCentralCrossRefGoogle Scholar
  36. Feske S, Gwack Y, Prakriya M, Srikanth S, Puppel SH, Tanasa B, Hogan PG, Lewis RS, Daly M, Rao A (2006) A mutation in Orai1 causes immune deficiency by abrogating CRAC channel function. Nature 441:179–185PubMedCrossRefGoogle Scholar
  37. Fox JE (2001) Cytoskeletal proteins and platelet signaling. Thromb Haemost 86:198–213PubMedGoogle Scholar
  38. Galan C, Zbidi H, Bartegi A, Salido GM, Rosado JA (2009) STIM1, Orai1 and hTRPC1 are important for thrombin- and ADP-induced aggregation in human platelets. Arch Biochem Biophys 490:137–144PubMedCrossRefGoogle Scholar
  39. Gilio K, van Kruchten R, Braun A, Berna-Erro A, Feijge MA, Stegner D, van der Meijden PE, Kuijpers MJ, Varga-Szabo D, Heemskerk JW, Nieswandt B (2010) Roles of platelet STIM1 and Orai1 in glycoprotein VI- and thrombin-dependent procoagulant activity and thrombus formation. J Biol Chem 285:23629–23638PubMedPubMedCentralCrossRefGoogle Scholar
  40. Golovina VA, Platoshyn O, Bailey CL, Wang J, Limsuwan A, Sweeney M, Rubin LJ, Yuan JX (2001) Upregulated TRP and enhanced capacitative Ca(2+) entry in human pulmonary artery myocytes during proliferation. Am J Physiol Heart Circ Physiol 280:H746–H755PubMedGoogle Scholar
  41. Grosse J, Braun A, Varga-Szabo D, Beyersdorf N, Schneider B, Zeitlmann L, Hanke P, Schropp P, Muhlstedt S, Zorn C, Huber M, Schmittwolf C, Jagla W, Yu P, Kerkau T, Schulze H, Nehls M, Nieswandt B (2007) An EF hand mutation in Stim1 causes premature platelet activation and bleeding in mice. J Clin Invest 117:3540–3550PubMedPubMedCentralCrossRefGoogle Scholar
  42. Gwack Y, Srikanth S, Feske S, Cruz-Guilloty F, Oh-hora M, Neems DS, Hogan PG, Rao A (2007) Biochemical and functional characterization of Orai proteins. J Biol Chem 282:16232–16243PubMedCrossRefGoogle Scholar
  43. Hampson A, O’Connor A, Smolenski A (2013) Synaptotagmin-like protein 4 and Rab8 interact and increase dense granule release in platelets. J Thromb Haemost 11:161–168PubMedCrossRefGoogle Scholar
  44. Harper MT, Sage SO (2010) Src family tyrosine kinases activate thrombin-induced non-capacitative cation entry in human platelets. Platelets 21:445–450PubMedCrossRefGoogle Scholar
  45. Harper MT, Londono JE, Quick K, Londono JC, Flockerzi V, Philipp SE, Birnbaumer L, Freichel M, Poole AW (2013) Transient receptor potential channels function as a coincidence signal detector mediating phosphatidylserine exposure. Sci Signal 6:ra50PubMedCrossRefGoogle Scholar
  46. Harrison P, Cramer EM (1993) Platelet alpha-granules. Blood Rev 7:52–62PubMedCrossRefGoogle Scholar
  47. Hayem G (1882) Sur le méchanisme de l’arrêt des hémorrhagies. C R Acad Sci 95:18Google Scholar
  48. Hoth M, Penner R (1992) Depletion of intracellular calcium stores activates a calcium current in mast cells. Nature 355:353–356PubMedCrossRefGoogle Scholar
  49. Hou X, Pedi L, Diver MM, Long SB (2012) Crystal structure of the calcium release-activated calcium channel Orai. Science 338:1308–1313PubMedPubMedCentralCrossRefGoogle Scholar
  50. Huang GN, Zeng W, Kim JY, Yuan JP, Han L, Muallem S, Worley PF (2006) STIM1 carboxyl-terminus activates native SOC, I(crac) and TRPC1 channels. Nat Cell Biol 8:1003–1010PubMedCrossRefGoogle Scholar
  51. Jardin I, Ben Amor N, Bartegi A, Pariente JA, Salido GM, Rosado JA (2007a) Differential involvement of thrombin receptors in Ca2+ release from two different intracellular stores in human platelets. Biochem J 401:167–174PubMedCrossRefGoogle Scholar
  52. Jardin I, Ben Amor N, Hernandez-Cruz JM, Salido GM, Rosado JA (2007b) Involvement of SNARE proteins in thrombin-induced platelet aggregation: evidence for the relevance of Ca2+ entry. Arch Biochem Biophys 465:16–25PubMedCrossRefGoogle Scholar
  53. Jardin I, Lopez JJ, Salido GM, Rosado JA (2008) Orai1 mediates the interaction between STIM1 and hTRPC1 and regulates the mode of activation of hTRPC1-forming Ca2+ channels. J Biol Chem 283:25296–25304PubMedCrossRefGoogle Scholar
  54. Jardin I, Gomez LJ, Salido GM, Rosado JA (2009) Dynamic interaction of hTRPC6 with the Orai1-STIM1 complex or hTRPC3 mediates its role in capacitative or non-capacitative Ca(2+) entry pathways. Biochem J 420:267–276PubMedCrossRefGoogle Scholar
  55. Jardin I, Lopez JJ, Zbidi H, Bartegi A, Salido GM, Rosado JA (2011) Attenuated store-operated divalent cation entry and association between STIM1, Orai1, hTRPC1 and hTRPC6 in platelets from type 2 diabetic patients. Blood Cells Mol Dis 46:252–260PubMedCrossRefGoogle Scholar
  56. Jardin I, Albarran L, Bermejo N, Salido GM, Rosado JA (2012) Homers regulate calcium entry and aggregation in human platelets: a role for Homers in the association between STIM1 and Orai1. Biochem J 445:29–38PubMedCrossRefGoogle Scholar
  57. Jardin I, Dionisio N, Frischauf I, Berna-Erro A, Woodard GE, Lopez JJ, Salido GM, Rosado JA (2013) The polybasic lysine-rich domain of plasma membrane-resident STIM1 is essential for the modulation of store-operated divalent cation entry by extracellular calcium. Cell Signal 25:1328–1337PubMedCrossRefGoogle Scholar
  58. Jha A, Ahuja M, Maleth J, Moreno CM, Yuan JP, Kim MS, Muallem S (2013) The STIM1 CTID domain determines access of SARAF to SOAR to regulate Orai1 channel function. J Cell Biol 202:71–79PubMedPubMedCentralCrossRefGoogle Scholar
  59. Junt T, Schulze H, Chen Z, Massberg S, Goerge T, Krueger A, Wagner DD, Graf T, Italiano JE Jr, Shivdasani RA, von Andrian UH (2007) Dynamic visualization of thrombopoiesis within bone marrow. Science 317:1767–1770PubMedCrossRefGoogle Scholar
  60. Kawasaki T, Lange I, Feske S (2009) A minimal regulatory domain in the C terminus of STIM1 binds to and activates ORAI1 CRAC channels. Biochem Biophys Res Commun 385:49–54PubMedPubMedCentralCrossRefGoogle Scholar
  61. Kim JY, Zeng W, Kiselyov K, Yuan JP, Dehoff MH, Mikoshiba K, Worley PF, Muallem S (2006) Homer 1 mediates store- and inositol 1,4,5-trisphosphate receptor-dependent translocation and retrieval of TRPC3 to the plasma membrane. J Biol Chem 281:32540–32549PubMedCrossRefGoogle Scholar
  62. Kiselyov KI, Semyonova SB, Mamin AG, Mozhayeva GN (1999) Miniature Ca2+ channels in excised plasma-membrane patches: activation by IP3. Pflugers Arch 437:305–314PubMedCrossRefGoogle Scholar
  63. Korzeniowski MK, Manjarres IM, Varnai P, Balla T (2010) Activation of STIM1-Orai1 involves an intramolecular switching mechanism. Sci Signal 3:ra82PubMedPubMedCentralCrossRefGoogle Scholar
  64. Lacruz RS, Feske S (2015) Diseases caused by mutations in ORAI1 and STIM1. Ann N Y Acad Sci 1356:45–79PubMedPubMedCentralCrossRefGoogle Scholar
  65. Lang F, Munzer P, Gawaz M, Borst O (2013) Regulation of STIM1/Orai1-dependent Ca2+ signalling in platelets. Thromb Haemost 110:925–930PubMedCrossRefGoogle Scholar
  66. Lee KP, Choi S, Hong JH, Ahuja M, Graham S, Ma R, So I, Shin DM, Muallem S, Yuan JP (2014) Molecular determinants mediating gating of Transient Receptor Potential Canonical (TRPC) channels by stromal interaction molecule 1 (STIM1). J Biol Chem 289:6372–6382PubMedPubMedCentralCrossRefGoogle Scholar
  67. Liao M, Cao E, Julius D, Cheng Y (2013) Structure of the TRPV1 ion channel determined by electron cryo-microscopy. Nature 504:107–112PubMedPubMedCentralCrossRefGoogle Scholar
  68. López JJ, Camello-Almaraz C, Pariente JA, Salido GM, Rosado JA (2005) Ca2+ accumulation into acidic organelles mediated by Ca2+- and vacuolar H+-ATPases in human platelets. Biochem J 390:243–252PubMedPubMedCentralCrossRefGoogle Scholar
  69. Lopez JJ, Redondo PC, Salido GM, Pariente JA, Rosado JA (2006a) Two distinct Ca2+ compartments show differential sensitivity to thrombin, ADP and vasopressin in human platelets. Cell Signal 18:373–381PubMedCrossRefGoogle Scholar
  70. Lopez JJ, Salido GM, Pariente JA, Rosado JA (2006b) Interaction of STIM1 with endogenously expressed human canonical TRP1 upon depletion of intracellular Ca2+ stores. J Biol Chem 281:28254–28264PubMedCrossRefGoogle Scholar
  71. Lopez E, Bermejo N, Berna-Erro A, Alonso N, Salido GM, Redondo PC, Rosado JA (2015) Relationship between calcium mobilization and platelet alpha- and delta-granule secretion. A role for TRPC6 in thrombin-evoked delta-granule exocytosis. Arch Biochem Biophys 585:75–81PubMedCrossRefGoogle Scholar
  72. Lu W, Xu D, Tu R, Hu Z (2013) Morphology of platelet Golgi apparatus and their significance after acute cerebral infarction. Neural Regen Res 8:2134–2143PubMedPubMedCentralGoogle Scholar
  73. Luckhoff A, Clapham DE (1994) Calcium channels activated by depletion of internal calcium stores in A431 cells. Biophys J 67:177–182PubMedPubMedCentralCrossRefGoogle Scholar
  74. Luik RM, Wu MM, Buchanan J, Lewis RS (2006) The elementary unit of store-operated Ca2+ entry: local activation of CRAC channels by STIM1 at ER-plasma membrane junctions. J Cell Biol 174:815–825PubMedPubMedCentralCrossRefGoogle Scholar
  75. Ma G, Wei M, He L, Liu C, Wu B, Zhang SL, Jing J, Liang X, Senes A, Tan P, Li S, Sun A, Bi Y, Zhong L, Si H, Shen Y, Li M, Lee MS, Zhou W, Wang J, Wang Y, Zhou Y (2015) Inside-out Ca(2+) signalling prompted by STIM1 conformational switch. Nat Commun 6:7826PubMedPubMedCentralCrossRefGoogle Scholar
  76. MacKenzie AB, Mahaut-Smith MP, Sage SO (1996) Activation of receptor-operated cation channels via P2X1 not P2T purinoceptors in human platelets. J Biol Chem 271:2879–2881PubMedCrossRefGoogle Scholar
  77. Manji SS, Parker NJ, Williams RT, van Stekelenburg L, Pearson RB, Dziadek M, Smith PJ (2000) STIM1: a novel phosphoprotein located at the cell surface. Biochim Biophys Acta 1481:147–155PubMedCrossRefGoogle Scholar
  78. Marcu MG, Zhang L, Nau-Staudt K, Trifaro JM (1996) Recombinant scinderin, an F-actin severing protein, increases calcium-induced release of serotonin from permeabilized platelets, an effect blocked by two scinderin-derived actin-binding peptides and phosphatidylinositol 4,5-bisphosphate. Blood 87:20–24PubMedGoogle Scholar
  79. Markello T, Chen D, Kwan JY, Horkayne-Szakaly I, Morrison A, Simakova O, Maric I, Lozier J, Cullinane AR, Kilo T, Meister L, Pakzad K, Bone W, Chainani S, Lee E, Links A, Boerkoel C, Fischer R, Toro C, White JG, Gahl WA, Gunay-Aygun M (2015) York platelet syndrome is a CRAC channelopathy due to gain-of-function mutations in STIM1. Mol Genet Metab 114:474–482PubMedCrossRefGoogle Scholar
  80. Mercer JC, Dehaven WI, Smyth JT, Wedel B, Boyles RR, Bird GS, Putney JW Jr (2006) Large store-operated calcium selective currents due to co-expression of Orai1 or Orai2 with the intracellular calcium sensor, Stim1. J Biol Chem 281:24979–24990PubMedPubMedCentralCrossRefGoogle Scholar
  81. Mignen O, Thompson JL, Shuttleworth TJ (2007) STIM1 regulates Ca2+ entry via arachidonate-regulated Ca2+-selective (ARC) channels without store depletion or translocation to the plasma membrane. J Physiol 579:703–715PubMedCrossRefGoogle Scholar
  82. Misceo D, Holmgren A, Louch WE, Holme PA, Mizobuchi M, Morales RJ, De Paula AM, Stray-Pedersen A, Lyle R, Dalhus B, Christensen G, Stormorken H, Tjonnfjord GE, Frengen E (2014) A dominant STIM1 mutation causes Stormorken syndrome. Hum Mutat 35:556–564PubMedCrossRefGoogle Scholar
  83. Montell C, Birnbaumer L, Flockerzi V, Bindels RJ, Bruford EA, Caterina MJ, Clapham DE, Harteneck C, Heller S, Julius D, Kojima I, Mori Y, Penner R, Prawitt D, Scharenberg AM, Schultz G, Shimizu N, Zhu MX (2002) A unified nomenclature for the superfamily of TRP cation channels. Mol Cell 9:229–231PubMedCrossRefGoogle Scholar
  84. Morin G, Bruechle NO, Singh AR, Knopp C, Jedraszak G, Elbracht M, Bremond-Gignac D, Hartmann K, Sevestre H, Deutz P, Herent D, Nurnberg P, Romeo B, Konrad K, Mathieu-Dramard M, Oldenburg J, Bourges-Petit E, Shen Y, Zerres K, Ouadid-Ahidouch H, Rochette J (2014) Gain-of-function mutation in STIM1 (P.R304W) is associated with Stormorken syndrome. Hum Mutat 35:1221–1232PubMedCrossRefGoogle Scholar
  85. Muik M, Fahrner M, Derler I, Schindl R, Bergsmann J, Frischauf I, Groschner K, Romanin C (2009) A cytosolic homomerization and a modulatory domain within STIM1 C terminus determine coupling to ORAI1 channels. J Biol Chem 284:8421–8426PubMedPubMedCentralCrossRefGoogle Scholar
  86. Nesin V, Wiley G, Kousi M, Ong EC, Lehmann T, Nicholl DJ, Suri M, Shahrizaila N, Katsanis N, Gaffney PM, Wierenga KJ, Tsiokas L (2014) Activating mutations in STIM1 and ORAI1 cause overlapping syndromes of tubular myopathy and congenital miosis. Proc Natl Acad Sci U S A 111:4197–4202PubMedPubMedCentralCrossRefGoogle Scholar
  87. Neumuller O, Hoffmeister M, Babica J, Prelle C, Gegenbauer K, Smolenski AP (2009) Synaptotagmin-like protein 1 interacts with the GTPase-activating protein Rap1GAP2 and regulates dense granule secretion in platelets. Blood 114:1396–1404PubMedCrossRefGoogle Scholar
  88. Nishimura S, Nagasaki M, Kunishima S, Sawaguchi A, Sakata A, Sakaguchi H, Ohmori T, Manabe I, Italiano JE Jr, Ryu T, Takayama N, Komuro I, Kadowaki T, Eto K, Nagai R (2015) IL-1alpha induces thrombopoiesis through megakaryocyte rupture in response to acute platelet needs. J Cell Biol 209:453–466PubMedPubMedCentralCrossRefGoogle Scholar
  89. Paez Espinosa EV, Murad JP, Ting HJ, Khasawneh FT (2012) Mouse transient receptor potential channel 6: role in hemostasis and thrombogenesis. Biochem Biophys Res Commun 417:853–856PubMedCrossRefGoogle Scholar
  90. Palty R, Isacoff EY (2015) Cooperative binding of stromal interaction molecule 1 (STIM1) to the N and C termini of calcium release-activated calcium modulator 1 (Orai1). J Biol Chem 291(1):334–341PubMedPubMedCentralCrossRefGoogle Scholar
  91. Palty R, Stanley C, Isacoff EY (2015) Critical role for Orai1 C-terminal domain and TM4 in CRAC channel gating. Cell Res 25:963–980PubMedPubMedCentralCrossRefGoogle Scholar
  92. Papp B, Enyedi A, Paszty K, Kovacs T, Sarkadi B, Gardos G, Magnier C, Wuytack F, Enouf J (1992) Simultaneous presence of two distinct endoplasmic-reticulum-type calcium-pump isoforms in human cells. Characterization by radio-immunoblotting and inhibition by 2,5-di-(t-butyl)-1,4-benzohydroquinone. Biochem J 288(Pt 1):297–302PubMedPubMedCentralCrossRefGoogle Scholar
  93. Park CY, Hoover PJ, Mullins FM, Bachhawat P, Covington ED, Raunser S, Walz T, Garcia KC, Dolmetsch RE, Lewis RS (2009) STIM1 clusters and activates CRAC channels via direct binding of a cytosolic domain to Orai1. Cell 136:876–890PubMedPubMedCentralCrossRefGoogle Scholar
  94. Paulsen CE, Armache JP, Gao Y, Cheng Y, Julius D (2015) Structure of the TRPA1 ion channel suggests regulatory mechanisms. Nature 520:511–517PubMedPubMedCentralCrossRefGoogle Scholar
  95. Peinelt C, Vig M, Koomoa DL, Beck A, Nadler MJ, Koblan-Huberson M, Lis A, Fleig A, Penner R, Kinet JP (2006) Amplification of CRAC current by STIM1 and CRACM1 (Orai1). Nat Cell Biol 8:771–773PubMedCrossRefGoogle Scholar
  96. Prakriya M, Lewis RS (2002) Separation and characterization of currents through store-operated CRAC channels and Mg2+-inhibited cation (MIC) channels. J Gen Physiol 119:487–507PubMedPubMedCentralCrossRefGoogle Scholar
  97. Prakriya M, Feske S, Gwack Y, Srikanth S, Rao A, Hogan PG (2006) Orai1 is an essential pore subunit of the CRAC channel. Nature 443:230–233PubMedCrossRefGoogle Scholar
  98. Putney JW Jr (1986) A model for receptor-regulated calcium entry. Cell Calcium 7:1–12PubMedCrossRefGoogle Scholar
  99. Ramanathan G, Gupta S, Thielmann I, Pleines I, Varga-Szabo D, May F, Mannhalter C, Dietrich A, Nieswandt B, Braun A (2012) Defective diacylglycerol-induced Ca2+ entry but normal agonist-induced activation responses in TRPC6-deficient mouse platelets. J Thromb Haemost 10:419–429PubMedCrossRefGoogle Scholar
  100. Redondo PC, Jardin I, Lopez JJ, Salido GM, Rosado JA (2008) Intracellular Ca2+ store depletion induces the formation of macromolecular complexes involving hTRPC1, hTRPC6, the type II IP3 receptor and SERCA3 in human platelets. Biochim Biophys Acta 1783:1163–1176PubMedCrossRefGoogle Scholar
  101. Ren Q, Wimmer C, Chicka MC, Ye S, Ren Y, Hughson FM, Whiteheart SW (2010) Munc13-4 is a limiting factor in the pathway required for platelet granule release and hemostasis. Blood 116:869–877PubMedPubMedCentralCrossRefGoogle Scholar
  102. Rodriguez Del Castillo A, Vitale ML, Tchakarov L, Trifaro JM (1992) Human platelets contain scinderin, a Ca(2+)-dependent actin filament-severing protein. Thromb Haemost 67:248–251PubMedGoogle Scholar
  103. Roos J, DiGregorio PJ, Yeromin AV, Ohlsen K, Lioudyno M, Zhang S, Safrina O, Kozak JA, Wagner SL, Cahalan MD, Velicelebi G, Stauderman KA (2005) STIM1, an essential and conserved component of store-operated Ca2+ channel function. J Cell Biol 169:435–445PubMedPubMedCentralCrossRefGoogle Scholar
  104. Rosado JA, Sage SO (2000a) The actin cytoskeleton in store-mediated calcium entry. J Physiol 526(Pt 2):221–229PubMedPubMedCentralCrossRefGoogle Scholar
  105. Rosado JA, Sage SO (2000b) Coupling between inositol 1,4,5-trisphosphate receptors and human transient receptor potential channel 1 when intracellular Ca2+ stores are depleted. Biochem J 350(Pt 3):631–635PubMedPubMedCentralCrossRefGoogle Scholar
  106. Rosado JA, Sage SO (2000c) Platelet signalling: calcium. In: Gresele P, Page CP, Fuster V, Vermylen J (eds) Platelets in thrombotic and non-thrombotic disorders pathophysiology, pharmacology and therapeutics. Cambridge University Press, Cambridge, pp 260–271Google Scholar
  107. Rosado JA, Sage SO (2000d) Protein kinase C activates non-capacitative calcium entry in human platelets. J Physiol 529(Pt 1):159–169PubMedPubMedCentralCrossRefGoogle Scholar
  108. Rothberg BS, Wang Y, Gill DL (2013) Orai channel pore properties and gating by STIM: implications from the Orai crystal structure. Sci Signal 6:pe9PubMedPubMedCentralCrossRefGoogle Scholar
  109. Sage SO, Merritt JE, Hallam TJ, Rink TJ (1989) Receptor-mediated calcium entry in fura-2-loaded human platelets stimulated with ADP and thrombin. Dual-wavelengths studies with Mn2+. Biochem J 258:923–926PubMedPubMedCentralCrossRefGoogle Scholar
  110. Sauc S, Bulla M, Nunes P, Orci L, Marchetti A, Antigny F, Bernheim L, Cosson P, Frieden M, Demaurex N (2015) STIM1L traps and gates Orai1 channels without remodeling the cortical ER. J Cell Sci 128:1568–1579PubMedPubMedCentralCrossRefGoogle Scholar
  111. Shen WW, Demaurex N (2012) Morphological and functional aspects of STIM1-dependent assembly and disassembly of store-operated calcium entry complexes. Biochem Soc Trans 40:112–118PubMedCrossRefGoogle Scholar
  112. Shirakawa R, Higashi T, Tabuchi A, Yoshioka A, Nishioka H, Fukuda M, Kita T, Horiuchi H (2004) Munc13-4 is a GTP-Rab27-binding protein regulating dense core granule secretion in platelets. J Biol Chem 279:10730–10737PubMedCrossRefGoogle Scholar
  113. Soboloff J, Spassova MA, Tang XD, Hewavitharana T, Xu W, Gill DL (2006) Orai1 and STIM reconstitute store-operated calcium channel function. J Biol Chem 281:20661–20665PubMedCrossRefGoogle Scholar
  114. Spassova MA, Soboloff J, He LP, Xu W, Dziadek MA, Gill DL (2006) STIM1 has a plasma membrane role in the activation of store-operated Ca(2+) channels. Proc Natl Acad Sci U S A 103:4040–4045PubMedPubMedCentralCrossRefGoogle Scholar
  115. Stathopulos PB, Li GY, Plevin MJ, Ames JB, Ikura M (2006) 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 281:35855–35862PubMedCrossRefGoogle Scholar
  116. Stathopulos PB, Zheng L, Ikura M (2009) Stromal interaction molecule (STIM) 1 and STIM2 calcium sensing regions exhibit distinct unfolding and oligomerization kinetics. J Biol Chem 284:728–732PubMedCrossRefGoogle Scholar
  117. Stathopulos PB, Schindl R, Fahrner M, Zheng L, Gasmi-Seabrook GM, Muik M, Romanin C, Ikura M (2013) STIM1/Orai1 coiled-coil interplay in the regulation of store-operated calcium entry. Nat Commun 4:2963PubMedPubMedCentralCrossRefGoogle Scholar
  118. Stormorken H (2002) [Stormorken’s syndrome]. Tidsskr Nor Laegeforen 122:2853–2856Google Scholar
  119. Stormorken H, Sjaastad O, Langslet A, Sulg I, Egge K, Diderichsen J (1985) A new syndrome: thrombocytopathia, muscle fatigue, asplenia, miosis, migraine, dyslexia and ichthyosis. Clin Genet 28:367–374PubMedCrossRefGoogle Scholar
  120. Stormorken H, Holmsen H, Sund R, Sakariassen KS, Hovig T, Jellum E, Solum O (1995) Studies on the haemostatic defect in a complicated syndrome. An inverse Scott syndrome platelet membrane abnormality? Thromb Haemost 74:1244–1251PubMedGoogle Scholar
  121. Thompson JL, Shuttleworth TJ (2013) Molecular basis of activation of the arachidonate-regulated Ca2+ (ARC) channel, a store-independent Orai channel, by plasma membrane STIM1. J Physiol 591:3507–3523PubMedPubMedCentralCrossRefGoogle Scholar
  122. Thompson JL, Mignen O, Shuttleworth TJ (2009) The Orai1 severe combined immune deficiency mutation and calcium release-activated Ca2+ channel function in the heterozygous condition. J Biol Chem 284:6620–6626PubMedPubMedCentralCrossRefGoogle Scholar
  123. To MS, Aromataris EC, Castro J, Roberts ML, Barritt GJ, Rychkov GY (2010) Mitochondrial uncoupler FCCP activates proton conductance but does not block store-operated Ca(2+) current in liver cells. Arch Biochem Biophys 495:152–158PubMedCrossRefGoogle Scholar
  124. Tolhurst G, Carter RN, Amisten S, Holdich JP, Erlinge D, Mahaut-Smith MP (2008) Expression profiling and electrophysiological studies suggest a major role for Orai1 in the store-operated Ca2+ influx pathway of platelets and megakaryocytes. Platelets 19:308–313PubMedPubMedCentralCrossRefGoogle Scholar
  125. Trepakova ES, Gericke M, Hirakawa Y, Weisbrod RM, Cohen RA, Bolotina VM (2001) Properties of a native cation channel activated by Ca2+ store depletion in vascular smooth muscle cells. J Biol Chem 276:7782–7790PubMedCrossRefGoogle Scholar
  126. Vaca L, Kunze DL (1994) Depletion of intracellular Ca2+ stores activates a Ca(2+)-selective channel in vascular endothelium. Am J Physiol 267:C920–C925PubMedGoogle Scholar
  127. Varga-Szabo D, Authi KS, Braun A, Bender M, Ambily A, Hassock SR, Gudermann T, Dietrich A, Nieswandt B (2008a) Store-operated Ca(2+) entry in platelets occurs independently of transient receptor potential (TRP) C1. Pflugers Arch 457:377–387PubMedCrossRefGoogle Scholar
  128. Varga-Szabo D, Braun A, Kleinschnitz C, Bender M, Pleines I, Pham M, Renne T, Stoll G, Nieswandt B (2008b) The calcium sensor STIM1 is an essential mediator of arterial thrombosis and ischemic brain infarction. J Exp Med 205:1583–1591PubMedPubMedCentralCrossRefGoogle Scholar
  129. Venkatachalam K, Montell C (2007) TRP channels. Annu Rev Biochem 76:387–417PubMedPubMedCentralCrossRefGoogle Scholar
  130. Vial C, Pitt SJ, Roberts J, Rolf MG, Mahaut-Smith MP, Evans RJ (2003) Lack of evidence for functional ADP-activated human P2X1 receptors supports a role for ATP during hemostasis and thrombosis. Blood 102:3646–3651PubMedCrossRefGoogle Scholar
  131. Vig M, Peinelt C, Beck A, Koomoa DL, Rabah D, Koblan-Huberson M, Kraft S, Turner H, Fleig A, Penner R, Kinet JP (2006) CRACM1 is a plasma membrane protein essential for store-operated Ca2+ entry. Science 312:1220–1223PubMedCrossRefGoogle Scholar
  132. Wes PD, Chevesich J, Jeromin A, Rosenberg C, Stetten G, Montell C (1995) TRPC1, a human homolog of a Drosophila store-operated channel. Proc Natl Acad Sci U S A 92:9652–9656PubMedPubMedCentralCrossRefGoogle Scholar
  133. White JG, Gunay-Aygun M (2011) The York platelet syndrome: a third case. Platelets 22:117–134PubMedCrossRefGoogle Scholar
  134. White JG, Pakzad K, Meister L (2013) The York platelet syndrome: a fourth case with unusual pathologic features. Platelets 24:44–50PubMedCrossRefGoogle Scholar
  135. Wu MM, Buchanan J, Luik RM, Lewis RS (2006) Ca2+ store depletion causes STIM1 to accumulate in ER regions closely associated with the plasma membrane. J Cell Biol 174:803–813PubMedPubMedCentralCrossRefGoogle Scholar
  136. Yang X, Jin H, Cai X, Li S, Shen Y (2012) Structural and mechanistic insights into the activation of stromal interaction molecule 1 (STIM1). Proc Natl Acad Sci U S A 109:5657–5662PubMedPubMedCentralCrossRefGoogle Scholar
  137. Yeromin AV, Zhang SL, Jiang W, Yu Y, Safrina O, Cahalan MD (2006) Molecular identification of the CRAC channel by altered ion selectivity in a mutant of Orai. Nature 443:226–229PubMedPubMedCentralCrossRefGoogle Scholar
  138. Yoshioka A, Shirakawa R, Nishioka H, Tabuchi A, Higashi T, Ozaki H, Yamamoto A, Kita T, Horiuchi H (2001) Identification of protein kinase Calpha as an essential, but not sufficient, cytosolic factor for Ca2+-induced alpha- and dense-core granule secretion in platelets. J Biol Chem 276:39379–39385PubMedCrossRefGoogle Scholar
  139. Yu F, Sun L, Courjaret R, Machaca K (2011) Role of the STIM1 C-terminal domain in STIM1 clustering. J Biol Chem 286(10):8375–8384PubMedPubMedCentralCrossRefGoogle Scholar
  140. Yuan JP, Kiselyov K, Shin DM, Chen J, Shcheynikov N, Kang SH, Dehoff MH, Schwarz MK, Seeburg PH, Muallem S, Worley PF (2003) Homer binds TRPC family channels and is required for gating of TRPC1 by IP3 receptors. Cell 114:777–789PubMedCrossRefGoogle Scholar
  141. Yuan JP, Zeng W, Dorwart MR, Choi YJ, Worley PF, Muallem S (2009) SOAR and the polybasic STIM1 domains gate and regulate Orai channels. Nat Cell Biol 11:337–343PubMedPubMedCentralCrossRefGoogle Scholar
  142. Zbidi H, Jardin I, Woodard GE, Lopez JJ, Berna-Erro A, Salido GM, Rosado JA (2011) STIM1 and STIM2 are located in the acidic Ca2+ stores and associates with Orai1 upon depletion of the acidic stores in human platelets. J Biol Chem 286:12257–12270PubMedPubMedCentralCrossRefGoogle Scholar
  143. Zeng W, Yuan JP, Kim MS, Choi YJ, Huang GN, Worley PF, Muallem S (2008) STIM1 gates TRPC channels, but not Orai1, by electrostatic interaction. Mol Cell 32:439–448PubMedPubMedCentralCrossRefGoogle Scholar
  144. Zhang SL, Yu Y, Roos J, Kozak JA, Deerinck TJ, Ellisman MH, Stauderman KA, Cahalan MD (2005) STIM1 is a Ca2+ sensor that activates CRAC channels and migrates from the Ca2+ store to the plasma membrane. Nature 437:902–905PubMedPubMedCentralCrossRefGoogle Scholar
  145. Zhang SL, Yeromin AV, Zhang XHF, Yu Y, Safrina O, Penna A, Roos J, Stauderman KA, Cahalan MD (2006) Genome-wide RNAi screen of Ca2+ influx identifies genes that regulate Ca2+ release-activated Ca2+ channel activity. Proc Natl Acad Sci U S A 103:9357–9362. doi: 10.1073/pnas.0603161103 PubMedPubMedCentralCrossRefGoogle Scholar
  146. Zhang X, Zhang W, Gonzalez-Cobos JC, Jardin I, Romanin C, Matrougui K, Trebak M (2014) Complex role of STIM1 in the activation of store-independent Orai1/3 channels. J Gen Physiol 143:345–359PubMedPubMedCentralCrossRefGoogle Scholar
  147. Zhu X, Chu PB, Peyton M, Birnbaumer L (1995) Molecular cloning of a widely expressed human homologue for the Drosophila trp gene. FEBS Lett 373:193–198PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  • Jose J. Lopez
    • 1
  • Gines M. Salido
    • 1
  • Juan A. Rosado
    • 1
    Email author
  1. 1.Cell Physiology Research Group, Department of PhysiologyUniversity of ExtremaduraCáceresSpain

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