Download PDF
Thromb Haemost 2013; 110(05): 925-930
DOI: 10.1160/TH13-02-0176
Theme Issue Article
Schattauer GmbH

Regulation of STIM1/Orai1-dependent Ca2+ signalling in platelets

Florian Lang
1   Department of Physiology, University of Tübingen, Germany
,
Patrick Münzer
1   Department of Physiology, University of Tübingen, Germany
,
Meinrad Gawaz
2   Department of Cardiology & Cardiovascular Medicine, University of Tübingen, Germany
,
Oliver Borst
1   Department of Physiology, University of Tübingen, Germany
2   Department of Cardiology & Cardiovascular Medicine, University of Tübingen, Germany
› Author Affiliations Financial support: Research in the authors laboratory is supported by the Deutsche Forschungsgemeinschaft (KFO 274 “Platelets – Basic Mechanisms and Translational Implications”) and a fortüne research grant to O.B. (2133–0).
Further Information

Publication History

Received: 27 February 2013

Accepted after major revision: 19 May 2013

Publication Date:
01 December 2017 (online)

Also available at
    Permissions and Reprints

Summary

Platelet secretion and aggregation as well as thrombus formation of blood platelets critically depend on increase of cytosolic Ca2+ concentration ([Ca2+]i) mainly resulting from intracellular Ca2+ release followed by store operated Ca2+ entry (SOCE) through Ca2+ release activated channels (CRAC). SOCE is in part accomplished by the pore forming unit Orai and its regulator stromal interaction molecule (STIM). Orai1 and STIM1 transcription is stimulated by NFkB (nuclear factor kappa B). Serum- and glucocorticoid-inducible kinase 1 (SGK1) up-regulates NFkB-activity in megakaryocytes and thus Orai1- expression and SOCE in platelets. SGK1 is thus a powerful regulator of platelet Ca2+-signalling and thrombus formation and presumably participates in the regulation of platelet activation by a variety of hormones as well as clinical conditions (e.g. type 2 diabetes or metabolic syndrome) associated with platelet hyperaggregability and increased risk of thromboocclusive events. SOCE in platelets is further regulated by scaffolding protein Homer and chaperone protein cyclophilin A (CyPA). Additional potential regulators of Orai1/STIM1 and thus SOCE in platelets include AMP activated kinase (AMPK), protein kinase A (PKA), reactive oxygen species, lipid rafts, pH and mitochondrial Ca2+ buffering. Future studies are required defining the significance of those mechanisms for platelet Orai1 abundance and function, for SOCE into platelets and for platelet function in cardiovascular diseases.

Keywords

Platelet physiologypolymorphisms - kinases - signal transduction - Ca2+ (arterial thrombosis)
 

  • References

  • 1 Ruggeri ZM. Platelets in atherothrombosis. Nat Med 2002; 8: 1227-1234.
    CrossrefPubMedGoogle Scholar
  • 2 Borst O. et al. The inflammatory chaemokine CXC motif ligand 16 triggers platelet activation and adhesion via CXC motif receptor 6-dependent phosphatidylinositide 3-kinase/Akt signalling. Circ Res 2012; 111: 1297-1307.
    CrossrefPubMedGoogle Scholar
  • 3 Bergmeier W, Stefanini L. Novel molecules in calcium signalling in platelets. J Thromb Haemost 2009; 7 (Suppl. 01) 187-190.
    CrossrefPubMedGoogle Scholar
  • 4 Borst O. et al. The serum- and glucocorticoid-inducible kinase 1 (SGK1) influences platelet calcium signalling and function by regulation of Orai1 expression in megakaryocytes. Blood 2012; 119: 251-261.
    CrossrefPubMedGoogle Scholar
  • 5 Gilio K. et al. Functional divergence of platelet protein kinase C (PKC) isoforms in thrombus formation on collagen. J Biol Chem 2010; 285: 23410-23419.
    CrossrefPubMedGoogle Scholar
  • 6 Stolla M. et al. The kinetics of alphaIIbbeta3 activation determines the size and stability of thrombi in mice: implications for antiplatelet therapy. Blood 2011; 117: 1005-1013.
    CrossrefPubMedGoogle Scholar
  • 7 Schoenwaelder SM. et al. Two distinct pathways regulate platelet phosphatidylserine exposure and procoagulant function. Blood 2009; 114: 663-666.
    CrossrefPubMedGoogle Scholar
  • 8 Wolfs JL. et al. Reversible inhibition of the platelet procoagulant response through manipulation of the Gardos channel. Blood 2006; 108: 2223-2228.
    CrossrefPubMedGoogle Scholar
  • 9 Gilio K. et al. Roles of platelet STIM1 and Orai1 in glycoprotein VI- and thrombin-dependent procoagulant activity and thrombus formation. J Biol Chem 2010; 285: 23629-23638.
    CrossrefPubMedGoogle Scholar
  • 10 Parekh AB. Store-operated CRAC channels: function in health and disease. Nat Rev Drug Discov 2010; 9: 399-410.
    CrossrefPubMedGoogle Scholar
  • 11 Varga-Szabo D. et al. Calcium signalling in platelets. J Thromb Haemost 2009; 7: 1057-1066.
    CrossrefPubMedGoogle Scholar
  • 12 Bergmeier W. et al. R93W mutation in Orai1 causes impaired calcium influx in platelets. Blood 2009; 113: 675-678.
    CrossrefPubMedGoogle Scholar
  • 13 Authi KS. Orai1: a channel to safer antithrombotic therapy. Blood 2009; 113: 1872-1873.
    CrossrefPubMedGoogle Scholar
  • 14 Braun A. et al. Orai1 (CRACM1) is the platelet SOC channel and essential for pathological thrombus formation. Blood 2009; 113: 2056-2063.
    CrossrefPubMedGoogle Scholar
  • 15 Feske S. CRAC channelopathies. Pflugers Arch 2010; 460: 417-435.
    CrossrefPubMedGoogle Scholar
  • 16 Varga-Szabo D. et al. The calcium sensor STIM1 is an essential mediator of arterial thrombosis and ischaemic brain infarction. J Exp Med 2008; 205: 1583-1591.
    CrossrefPubMedGoogle Scholar
  • 17 Grosse J. et al. An EFhand mutation in Stim1 causes premature platelet activation and bleeding in mice. J Clin Invest 2007; 117: 3540-3550.
    CrossrefPubMedGoogle Scholar
  • 18 Berna-Erro A. et al. Capacitative and non-capacitative signalling complexes in human platelets. Biochim Biophys Acta 2012; 1823: 1242-1251.
    CrossrefPubMedGoogle Scholar
  • 19 Le Deist F. et al. A primary T-cell immunodeficiency associated with defective transmembrane calcium influx. Blood 1995; 85: 1053-1062.
    PubMedGoogle Scholar
  • 20 Ahmad F. et al. Relative contributions of stromal interaction molecule 1 and CalDAG-GEFI to calcium-dependent platelet activation and thrombosis. J Thromb Haemost 2011; 9: 2077-2086.
    CrossrefPubMedGoogle Scholar
  • 21 Smith KA, Yuan JX. CRACing the cluster: functionally active Orai1 channels in the absence of clustering with STIM1. Circ Res 2012; 111: 9-11.
    CrossrefPubMedGoogle Scholar
  • 22 van Kruchten R. et al. Antithrombotic potential of blockers of store-operated calcium channels in platelets. Arterioscler Thromb Vasc Biol 2012; 32: 1717-1723.
    CrossrefPubMedGoogle Scholar
  • 23 Galan C. et al. STIM1, Orai1 and hTRPC1 are important for thrombin- and ADP-induced aggregation in human platelets. Arch Biochem Biophys 2009; 490: 137-144.
    CrossrefPubMedGoogle Scholar
  • 24 Jardin I. et al. Orai1 mediates the interaction between STIM1 and hTRPC1 and regulates the mode of activation of hTRPC1-forming Ca2+ channels. J Biol Chem 2008; 283: 25296-25304.
    CrossrefPubMedGoogle Scholar
  • 25 Jardin I. et al. Store-operated Ca2+ entry is sensitive to the extracellular Ca2+ concentration through plasma membrane STIM1. Biochim Biophys Acta 2009; 1793: 1614-1622.
    CrossrefPubMedGoogle Scholar
  • 26 Dobrydneva Y. et al. Diethylstilbestrol and other nonsteroidal estrogens: novel class of store-operated calcium channel modulators. J Cardiovasc Pharmacol 2010; 55: 522-530.
    PubMedGoogle Scholar
  • 27 Tolios A. et al. Increased platelet Ca2+ channel Orai1 expression upon platelet activation and in patients with acute myocardial infarction. Thromb Haemost 2013; 110: 386-389.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 28 Ramanathan G. et al. Defective diacylglycerol-induced Ca2+ entry but normal agonist-induced activation responses in TRPC6-deficient mouse platelets. J Thromb Haemost 2012; 10: 419-429.
    CrossrefPubMedGoogle Scholar
  • 29 Jardin I. et al. 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 2009; 420: 267-276.
    CrossrefPubMedGoogle Scholar
  • 30 Sage SO. et al. TRP channels and calcium entry in human platelets. Blood 2002; 100: 4245-4246.
    CrossrefPubMedGoogle Scholar
  • 31 Hassock SR. et al. Expression and role of TRPC proteins in human platelets: evidence that TRPC6 forms the store-independent calcium entry channel. Blood 2002; 100: 2801-2811.
    CrossrefPubMedGoogle Scholar
  • 32 Authi KS. TRP channels in platelet function. Handb Exp Pharmacol 2007; 425-443.
    PubMedGoogle Scholar
  • 33 Dionisio N. et al. Transient receptor potential channels in human platelets: expression and functional role. Curr Mol Med 2012; 12: 1319-1328.
    CrossrefPubMedGoogle Scholar
  • 34 Redondo PC. et al. 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 2008; 1783: 1163-1176.
    CrossrefPubMedGoogle Scholar
  • 35 Baker RG. et al. NF-kappaB, inflammation, and metabolic disease. Cell Metab 2011; 13: 11-22.
    CrossrefPubMedGoogle Scholar
  • 36 Ferreira IA. et al. Platelet inhibition by insulin is absent in type 2 diabetes mellitus. Arterioscler Thromb Vasc Biol 2006; 26: 417-422.
    PubMedGoogle Scholar
  • 37 Spinelli SL. et al. Platelets and megakaryocytes contain functional nuclear factor-kappaB. Arterioscler Thromb Vasc Biol 2010; 30: 591-598.
    CrossrefPubMedGoogle Scholar
  • 38 Kim KW. et al. Extracellular signal-regulated kinase/90-KDA ribosomal S6 kinase/nuclear factor-kappa B pathway mediates phorbol 12-myristate 13-acetate-induced megakaryocytic differentiation of K562 cells. J Biol Chem 2001; 276: 13186-13191.
    CrossrefPubMedGoogle Scholar
  • 39 Beaulieu LM. et al. Regulatory effects of TLR2 on megakaryocytic cell function. Blood 2011; 117: 5963-5974.
    CrossrefPubMedGoogle Scholar
  • 40 Eylenstein A. et al. Transcription factor NF-kappaB regulates expression of pore-forming Ca2+ channel unit, Orai1, and its activator, STIM1, to control Ca2+ entry and affect cellular functions. J Biol Chem 2012; 287: 2719-2730.
    CrossrefPubMedGoogle Scholar
  • 41 Jackson SP. et al. PI 3-kinase p110beta: a new target for antithrombotic therapy. Nat Med 2005; 11: 507-514.
    CrossrefPubMedGoogle Scholar
  • 42 Gilio K. et al. Non-redundant roles of phosphoinositide 3-kinase isoforms alpha and beta in glycoprotein VI-induced platelet signalling and thrombus formation. J Biol Chem 2009; 284: 33750-33762.
    CrossrefPubMedGoogle Scholar
  • 43 Lian L. et al. The relative role of PLCbeta and PI3Kgamma in platelet activation. Blood 2005; 106: 110-117.
    CrossrefPubMedGoogle Scholar
  • 44 Konopatskaya O. et al. PKCalpha regulates platelet granule secretion and thrombus formation in mice. J Clin Invest 2009; 119: 399-407.
    PubMedGoogle Scholar
  • 45 Moore SF. et al. Dual Regulation of Glycogen Synthase Kinase 3 (GSK3)alpha/beta by Protein Kinase C (PKC)alpha and Akt Promotes Thrombin-mediated Integrin alphaIIbbeta3 Activation and Granule Secretion in Platelets. J Biol Chem 2013; 288: 3918-3928.
    CrossrefPubMedGoogle Scholar
  • 46 Chen J. et al. Impaired platelet responses to thrombin and collagen in AKT-1-deficient mice. Blood 2004; 104: 1703-1710.
    CrossrefPubMedGoogle Scholar
  • 47 Lang F. et al. (Patho)physiological significance of the serum- and glucocorticoid-inducible kinase isoforms. Physiol Rev 2006; 86: 1151-1178.
    CrossrefPubMedGoogle Scholar
  • 48 Schmidt EM. et al. SGK1 sensitivity of platelet migration. Cell Physiol Biochem 2012; 30: 259-268.
    CrossrefPubMedGoogle Scholar
  • 49 Zhang L. et al. Antiapoptotic effect of serum and glucocorticoid-inducible protein kinase is mediated by novel mechanism activating I{kappa}B kinase. Cancer Res 2005; 65: 457-464.
    PubMedGoogle Scholar
  • 50 Lang F, Shumilina E. Regulation of ion channels by the serum- and glucocorticoid-inducible kinase SGK1. FASEB J 2013; 27: 3-12.
    CrossrefPubMedGoogle Scholar
  • 51 Lang F. et al. Targeting SGK1 in diabetes. Expert Opin Ther Targets 2009; 13: 1303-1311.
    CrossrefPubMedGoogle Scholar
  • 52 Dahlberg J. et al. Genetic variants in serum and glucocortocoid regulated kinase 1, a regulator of the epithelial sodium channel, are associated with ischaemic stroke. J Hypertens 2011; 29: 884-889.
    CrossrefPubMedGoogle Scholar
  • 53 Schmid E. et al. SGK3 regulates Ca(2+) entry and migration of dendritic cells. Cell Physiol Biochem 2012; 30: 1423-1435.
    CrossrefPubMedGoogle Scholar
  • 54 Ogawa A. et al. PDGF enhances store-operated Ca2+ entry by upregulating STIM1/Orai1 via activation of Akt/mTOR in human pulmonary arterial smooth muscle cells. Am J Physiol Cell Physiol 2012; 302: C405-C411.
    CrossrefPubMedGoogle Scholar
  • 55 Elvers M. et al. Intracellular cyclophilin A is an important Ca(2+) regulator in platelets and critically involved in arterial thrombus formation. Blood 2012; 120: 1317-1326.
    CrossrefPubMedGoogle Scholar
  • 56 Pozo-Guisado E. et al. Phosphorylation of STIM1 at ERK1/2 target sites modulates store-operated calcium entry. J Cell Sci 2010; 123: 3084-3093.
    CrossrefPubMedGoogle Scholar
  • 57 Rosado JA. et al. SERCA2b activity is regulated by cyclophilins in human platelets. Arterioscler Thromb Vasc Biol 2010; 30: 419-425.
    CrossrefPubMedGoogle Scholar
  • 58 Jardin I. et al. Homers regulate calcium entry and aggregation in human platelets. A role for Homers in the association between STIM1 and Orai1. Biochem J 2012; 445: 29-38.
    PubMedGoogle Scholar
  • 59 Fleming I. et al. AMP-activated protein kinase (AMPK) regulates the insulin-induced activation of the nitric oxide synthase in human platelets. Thromb Haemost 2003; 90: 863-871.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 60 Steinberg GR, Kemp BE. AMPK in Health and Disease. Physiol Rev 2009; 89: 1025-1078.
    CrossrefPubMedGoogle Scholar
  • 61 Randriamboavonjy V. et al. AMPK alpha2 subunit is involved in platelet signalling, clot retraction, and thrombus stability. Blood 2010; 116: 2134-2140.
    CrossrefPubMedGoogle Scholar
  • 62 Nurbaeva MK. et al. Enhanced Ca(2)(+) entry and Na+/Ca(2)(+) exchanger activity in dendritic cells from AMP-activated protein kinase-deficient mice. FASEB J 2012; 26: 3049-3058.
    CrossrefPubMedGoogle Scholar
  • 63 Mungai PT. et al. Hypoxia triggers AMPK activation through reactive oxygen species-mediated activation of calcium release-activated calcium channels. Mol Cell Biol 2011; 31: 3531-3545.
    CrossrefPubMedGoogle Scholar
  • 64 Tian G. et al. cAMP induces stromal interaction molecule 1 (STIM1) puncta but neither Orai1 protein clustering nor store-operated Ca2+ entry (SOCE) in islet cells. J Biol Chem 2012; 287: 9862-9872.
    CrossrefPubMedGoogle Scholar
  • 65 Lopez E. et al. STIM1 tyrosine-phosphorylation is required for STIM1-Orai1 association in human platelets. Cell Signal 2012; 24: 1315-1322.
    CrossrefPubMedGoogle Scholar
  • 66 Bogeski I. et al. Differential redox regulation of ORAI ion channels: a mechanism to tune cellular calcium signalling. Sci Signal 2010; 3: ra24
    PubMedGoogle Scholar
  • 67 Pani B, Singh BB. Lipid rafts/caveolae as microdomains of calcium signalling. Cell Calcium 2009; 45: 625-633.
    CrossrefPubMedGoogle Scholar
  • 68 Dionisio N. et al. Lipid rafts are essential for the regulation of SOCE by plasma membrane resident STIM1 in human platelets. Biochim Biophys Acta 2011; 1813: 431-437.
    CrossrefPubMedGoogle Scholar
  • 69 Marumo M. et al. Extracellular pH affects platelet aggregation associated with modulation of store-operated Ca(2+) entry. Thromb Res 2001; 104: 353-360.
    CrossrefPubMedGoogle Scholar
  • 70 Rosado JA. Acidic Ca(2+) stores in platelets. Cell Calcium 2011; 50: 168-174.
    CrossrefPubMedGoogle Scholar
  • 71 Zbidi H. et al. 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 2011; 286: 12257-12270.
    CrossrefPubMedGoogle Scholar
  • 72 Bakowski D. et al. Endoplasmic reticulum-mitochondria coupling: local Ca(2+) signalling with functional consequences. Pflugers Arch 2012; 464: 27-32.
    CrossrefPubMedGoogle Scholar
  • 73 Oakes SA. Mitochondria control calcium entry at the immunological synapse. Proc Natl Acad Sci USA 2007; 104: 15171-15172.
    CrossrefPubMedGoogle Scholar
  • 74 Eylenstein A. et al. Stimulation of Ca2+-channel Orai1/STIM1 by serum- and glucocorticoid-inducible kinase 1 (SGK1). FASEB J 2011; 25: 2012-2021.
    CrossrefPubMedGoogle Scholar
  • 75 Woodard GE. et al. TRPC3 regulates agonist-stimulated Ca2+ mobilisation by mediating the interaction between type I inositol 1,4,5-trisphosphate receptor, RACK1, and Orai1. J Biol Chem 2010; 285: 8045-8053.
    CrossrefPubMedGoogle Scholar
  • 76 Zbidi H. et al. Enhanced expression of STIM1/Orai1 and TRPC3 in platelets from patients with type 2 diabetes mellitus. Blood Cells Mol Dis 2009; 43: 211-213.
    CrossrefPubMedGoogle Scholar
  • 77 Alexandru N. et al. Platelet free cytosolic calcium concentration during ageing of type 2 diabetic patients. Platelets 2007; 18: 473-480.
    CrossrefPubMedGoogle Scholar
  • 78 El Haouari M, Rosado JA. Platelet signalling abnormalities in patients with type 2 diabetes mellitus: a review. Blood Cells Mol Dis 2008; 41: 119-123.
    CrossrefPubMedGoogle Scholar
  • 79 Jardin I. et al. 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 2011; 46: 252-260.
    CrossrefPubMedGoogle Scholar
  • 80 Lu KC. et al. Hyperparathyroidism, glucose tolerance and platelet intracellular free calcium in chronic renal failure. Q J Med 1994; 87: 359-365.
    PubMedGoogle Scholar
  • 81 Ware JA. et al. Abnormalities of cytoplasmic Ca2+ in platelets from patients with uremia. Blood 1989; 73: 172-176.
    PubMedGoogle Scholar
  • 82 Gawaz M. Intelligent platelet inhibitors are on the horizon. Arterioscler Thromb Vasc Biol 2011; 31: 1949-1950.
    CrossrefPubMedGoogle Scholar
  • 83 Lang F, Voelkl J. Therapeutic potential of serum and glucocorticoid inducible kinase inhibition. Expert Opin Investig Drugs. 2013 in press.
    PubMedGoogle Scholar