Download PDF
Aktuelle Neurologie 2017; 44(06): 415-424
DOI: 10.1055/s-0043-109096
Übersicht
© Georg Thieme Verlag KG Stuttgart · New York

Kalziumhomöostase in der Multiplen Sklerose

Calcium Homeostasis in Multiple Sclerosis
Petra Hundehege
Institut für Translationale Neurologie, Münster und Klinik für Allgemeine Neurologie, Münster
,
Lisa Epping
Institut für Translationale Neurologie, Münster und Klinik für Allgemeine Neurologie, Münster
,
Sven G. Meuth
Institut für Translationale Neurologie, Münster und Klinik für Allgemeine Neurologie, Münster
› Author Affiliations
Further Information

Publication History

Publication Date:
07 August 2017 (online)

Also available at
    Permissions and Reprints

Zusammenfassung

Kalzium ist als Signalmolkül entscheidend für nahezu alle zellulären Prozesse. Eine Störung der Kalziumhomöostase ist ursächlich für eine Vielzahl von pathologischen Zuständen. Dieser Übersichtsartikel fasst rezente Erkenntnisse über den Einfluss von Kalzium in der Multiplen Sklerose zusammen.

Abstract

Calcium is the signal molecule crucial for almost all cellular processes. Disturbances of calcium homeostasis are responsible for a variety of pathological conditions. This review article summarizes recent findings on the influence of calcium in multiple sclerosis.

Schlüsselwörter

Pathologie - Immunzellen - Blut-Hirn-Schranke - zentrales Nervensystem - speicher-abhängiger Kalziumeinstrom

Key words

pathology - immune cells - blood-brain barrier - central nervous system - store-operated calcium entry
 

  • Literatur

  • 1 Frohman EM, Racke MK, Raine CS. Multiple sclerosis – the plaque and its pathogenesis. N Engl J Med 2006; 354: 942-955
    CrossrefPubMedGoogle Scholar
  • 2 Mahad DH, Trapp BD, Lassmann H. Pathological mechanisms in progressive multiple sclerosis. Lancet Neurol 2015; 14: 183-193
    CrossrefPubMedGoogle Scholar
  • 3 Hemmer B, Kerschensteiner M, Korn T. Role of the innate and adaptive immune responses in the course of multiple sclerosis. Lancet Neurol 2015; 14: 406-419
    CrossrefPubMedGoogle Scholar
  • 4 Mallucci G, Peruzzotti-Jametti L, Bernstock JD. et al. The role of immune cells, glia and neurons in white and gray matter pathology in multiple sclerosis. Prog Neurobiol 2015; 127 – 128: 1-22
    PubMedGoogle Scholar
  • 5 Bittner S, Ruck T, Schuhmann M. et al. Endothelial TWIK-related potassium channel-1 (TREK1) regulates immune-cell trafficking into the CNS. Nat Med 2013; 19: 1161-1165
    CrossrefPubMedGoogle Scholar
  • 6 Breuer J, Schwab N, Schneider-Hohendorf T. et al. Ultraviolet B light attenuates the systemic immune response in central nervous system autoimmunity. Ann Neurol 2014; 75: 739-758
    CrossrefPubMedGoogle Scholar
  • 7 Clapham DE. Calcium signaling. Cell 2007; 131: 1047-1058
    CrossrefPubMedGoogle Scholar
  • 8 Wu ZZ, Li DP, Chen SR. et al. Aminopyridines potentiate synaptic and neuromuscular transmission by targeting the voltage-activated calcium channel beta subunit. J Biol Chem 2009; 284: 36453-36461
    CrossrefPubMedGoogle Scholar
  • 9 Sebzda E, Mariathasan S, Ohteki T. et al. Selection of the T cell repertoire. Annu Rev Immunol 1999; 17: 829-874
    CrossrefPubMedGoogle Scholar
  • 10 Schwarz A, Schumacher M, Pfaff D. et al. Fine-tuning of regulatory T cell function: the role of calcium signals and naive regulatory T cells for regulatory T cell deficiency in multiple sclerosis. J Immunol 2013; 190: 4965-4970
    CrossrefPubMedGoogle Scholar
  • 11 Feske S, Wulff H, Skolnik EY. Ion channels in innate and adaptive immunity. Annu Rev Immunol 2015; 33: 291-353
    CrossrefPubMedGoogle Scholar
  • 12 Hogan PG, Lewis RS, Rao A. Molecular basis of calcium signaling in lymphocytes: STIM and ORAI. Annu Rev Immunol 2010; 28: 491-533
    CrossrefPubMedGoogle Scholar
  • 13 Feske S. Immunodeficiency due to defects in store-operated calcium entry. Ann NY Acad Sci 2011; 1238: 74-90
    CrossrefPubMedGoogle Scholar
  • 14 Schuhmann M, Stegner D, Berna-Erro A. et al. Stromal interaction molecules 1 and 2 are key regulators of autoreactive T cell activation in murine autoimmune central nervous system inflammation. J Immunology 2010; 184: 1536-1542
    PubMedGoogle Scholar
  • 15 Ma J, McCarl C-A, Khalil S. et al. T-cell-specific deletion of STIM1 and STIM2 protects mice from EAE by impairing the effector functions of Th1 and Th17 cells. Eur J Immunology 2010; 40: 3028-3042
    CrossrefPubMedGoogle Scholar
  • 16 Kim KD, Srikanth S, Tan YV. et al. Calcium signaling via Orai1 is essential for induction of the nuclear orphan receptor pathway to drive Th17 differentiation. J Immunol 2014; 192: 110-122
    CrossrefPubMedGoogle Scholar
  • 17 Tian C, Du L, Zhou Y. et al. Store-operated CRAC channel inhibitors: opportunities and challenges. Future Med Chem 2016; 8: 817-832
    CrossrefPubMedGoogle Scholar
  • 18 Chen G, Panicker S, Lau KY. et al. Characterization of a novel CRAC inhibitor that potently blocks human T cell activation and effector functions. Mol Immunol 2013; 54: 355-367
    CrossrefPubMedGoogle Scholar
  • 19 Cox JH, Hussell S, Sondergaard H. et al. Antibody-mediated targeting of the Orai1 calcium channel inhibits T cell function. PLoS One 2013; 8: e82944
    CrossrefPubMedGoogle Scholar
  • 20 Fuchs S, Rensing-Ehl A, Speckmann C. et al. Antiviral and regulatory T cell immunity in a patient with stromal interaction molecule 1 deficiency. J Immunol 2012; 188: 1523-1533
    CrossrefPubMedGoogle Scholar
  • 21 Lacruz RS, Feske S. Diseases caused by mutations in ORAI1 and STIM1. Ann N Y Acad Sci 2015; 1356: 45-79
    CrossrefPubMedGoogle Scholar
  • 22 Wang H, Zhang X, Xue L. et al. Low-Voltage-Activated CaV3. 1 Calcium channels shape T helper cell cytokine profiles. Immunity 2016; 44: 782-794
    PubMedGoogle Scholar
  • 23 Ehling P, Meuth P, Eichinger P. et al. Human T cells in silico: Modelling their electrophysiological behaviour in health and disease. J Theor Biol 2016; 404: 236-250
    CrossrefPubMedGoogle Scholar
  • 24 Wolf IM, Diercks BP, Gattkowski E. et al. Frontrunners of T cell activation: Initial, localized Ca2+ signals mediated by NAADP and the type 1 ryanodine receptor. Sci Signal 2015; 8: ra102
    CrossrefPubMedGoogle Scholar
  • 25 Chokshi R, Matsushita M, Kozak JA. Sensitivity of TRPM7 channels to Mg2+ characterized in cell-free patches of Jurkat T lymphocytes. Am J Physiol Cell Physiol 2012; 302: C1642-1651
    CrossrefPubMedGoogle Scholar
  • 26 Chokshi R, Matsushita M, Kozak J. Detailed examination of Mg2+ and pH sensitivity of human TRPM7 channels. Am J Physiol Cell Physiol 2012; 302: 11
    PubMedGoogle Scholar
  • 27 Carmans S, Hendriks JJ, Slaets H. et al. Systemic treatment with the inhibitory neurotransmitter gamma-aminobutyric acid aggravates experimental autoimmune encephalomyelitis by affecting proinflammatory immune responses. J Neuroimmunol 2013; 255: 45-53
    CrossrefPubMedGoogle Scholar
  • 28 Prud'homme GJ, Glinka Y, Wang Q. Immunological GABAergic interactions and therapeutic applications in autoimmune diseases. Autoimmun Rev 2015; 14: 1048-1056
    CrossrefPubMedGoogle Scholar
  • 29 Alam S, Laughton DL, Walding A. et al. Human peripheral blood mononuclear cells express GABAA receptor subunits. Mol Immunol 2006; 43: 1432-1442
    CrossrefPubMedGoogle Scholar
  • 30 Abbott NJ, Patabendige AA, Dolman DE. et al. Structure and function of the blood-brain barrier. Neurobiol Dis 2010; 37: 13-25
    CrossrefPubMedGoogle Scholar
  • 31 Hawkins BT, Davis TP. The blood-brain barrier/neurovascular unit in health and disease. Pharmacol Rev 2005; 57: 173-185
    CrossrefPubMedGoogle Scholar
  • 32 Hartsock A, Nelson WJ. Adherens and tight junctions: structure, function and connections to the actin cytoskeleton. Biochim Biophys Acta 2008; 1778: 660-669
    CrossrefPubMedGoogle Scholar
  • 33 Coisne C, Engelhardt B. Tight junctions in brain barriers during central nervous system inflammation. Antioxid Redox Signal 2011; 15: 1285-1303
    CrossrefPubMedGoogle Scholar
  • 34 Minagar A, Alexander JS. Blood-brain barrier disruption in multiple sclerosis. Mult Scler 2003; 9: 540-549
    CrossrefPubMedGoogle Scholar
  • 35 De Bock M, Wang N, Decrock E. et al. Endothelial calcium dynamics, connexin channels and blood-brain barrier function. Prog Neurobiol 2013; 108: 1-20
    CrossrefPubMedGoogle Scholar
  • 36 Ramirez SH, Hasko J, Skuba A. et al. Activation of cannabinoid receptor 2 attenuates leukocyte-endothelial cell interactions and blood-brain barrier dysfunction under inflammatory conditions. J Neurosci 2012; 32: 4004-4016
    CrossrefPubMedGoogle Scholar
  • 37 Rochfort KD, Cummins PM. The blood-brain barrier endothelium: a target for pro-inflammatory cytokines. Biochem Soc Trans 2015; 43: 702-706
    CrossrefPubMedGoogle Scholar
  • 38 Lanz TV, Becker S, Osswald M. et al. Protein kinase Cbeta as a therapeutic target stabilizing blood-brain barrier disruption in experimental autoimmune encephalomyelitis. Proc Natl Acad Sci USA 2013; 110: 14735-14740
    CrossrefPubMedGoogle Scholar
  • 39 Prager B, Spampinato SF, Ransohoff RM. Sphingosine 1-phosphate signaling at the blood-brain barrier. Trends Mol Med 2015; 21: 354-363
    CrossrefPubMedGoogle Scholar
  • 40 Chen JT, Chen TG, Chang YC. et al. Roles of NMDARs in maintenance of the mouse cerebrovascular endothelial cell-constructed tight junction barrier. Toxicol 2016; 339: 40-50
    CrossrefPubMedGoogle Scholar
  • 41 Neuhaus W, Freidl M, Szkokan P. et al. Effects of NMDA receptor modulators on a blood-brain barrier in vitro model. Brain Res 2011; 1394: 49-61
    CrossrefPubMedGoogle Scholar
  • 42 Reijerkerk A, Kooij G, van der Pol SM. et al. The NR1 subunit of NMDA receptor regulates monocyte transmigration through the brain endothelial cell barrier. J Neurochem 2010; 113: 447-453
    CrossrefPubMedGoogle Scholar
  • 43 Wang XS, Fang HL, Chen Y. et al. Idazoxan reduces blood-brain barrier damage during experimental autoimmune encephalomyelitis in mouse. Eur J Pharmacol 2014; 736: 70-76
    CrossrefPubMedGoogle Scholar
  • 44 Macrez R, Ortega MC, Bardou I. et al. Neuroendothelial NMDA receptors as therapeutic targets in experimental autoimmune encephalomyelitis. Brain 2016; 139: 2406-2419
    CrossrefPubMedGoogle Scholar
  • 45 Balbuena P, Li W, Rzigalinski BA. et al. Malathion/oxon and lead acetate increase gene expression and protein levels of transient receptor potential canonical channel subunits TRPC1 and TRPC4 in rat endothelial cells of the blood-brain barrier. Int J Toxicol 2012; 31: 238-249
    CrossrefPubMedGoogle Scholar
  • 46 Hicks K, O'Neil RG, Dubinsky WS. et al. TRPC-mediated actin-myosin contraction is critical for BBB disruption following hypoxic stress. Am J Physiol Cell Physiol 2010; 298: C1583-1593
    CrossrefPubMedGoogle Scholar
  • 47 Etienne-Manneville S, Manneville JB, Adamson P. et al. ICAM-1-coupled cytoskeletal rearrangements and transendothelial lymphocyte migration involve intracellular calcium signaling in brain endothelial cell lines. J Immunol 2000; 165: 3375-3383
    CrossrefPubMedGoogle Scholar
  • 48 Weber EW, Han F, Tauseef M. et al. TRPC6 is the endothelial calcium channel that regulates leukocyte transendothelial migration during the inflammatory response. J Exp Med 2015; 212: 1883-1899
    CrossrefPubMedGoogle Scholar
  • 49 Kostic M, Zivkovic N, Stojanovic I. Multiple sclerosis and glutamate excitotoxicity. Rev Nneurosci 2013; 24: 71-88
    PubMedGoogle Scholar
  • 50 Dutta R, Trapp BD. Mechanisms of neuronal dysfunction and degeneration in multiple sclerosis. Prog Neurobiol 2011; 93: 1-12
    CrossrefPubMedGoogle Scholar
  • 51 Stavrovskaya IG, Kristal BS. The powerhouse takes control of the cell: is the mitochondrial permeability transition a viable therapeutic target against neuronal dysfunction and death?. Free Radic Biol Med 2005; 38: 687-697
    CrossrefPubMedGoogle Scholar
  • 52 Siffrin V, Birkenstock J, Luchtman DW. et al. FRET based ratiometric Ca(2+) imaging to investigate immune-mediated neuronal and axonal damage processes in experimental autoimmune encephalomyelitis. J Neurosci Methods 2015; 249: 8-15
    CrossrefPubMedGoogle Scholar
  • 53 Angelova PR, Abramov AY. Alpha-synuclein and beta-amyloid – different targets, same players: calcium, free radicals and mitochondria in the mechanism of neurodegeneration. Biochem Biophys Res Commun 2017; 483: 1110-1115
    CrossrefPubMedGoogle Scholar
  • 54 Radbruch H, Bremer D, Guenther R. et al. Ongoing oxidative stress causes subclinical neuronal dysfunction in the recovery phase of EAE. Front Immunol 2016; 7: 92
    PubMedGoogle Scholar
  • 55 Callea L, Arese M, Orlandini A. et al. Platelet activating factor is elevated in cerebral spinal fluid and plasma of patients with relapsing-remitting multiple sclerosis. J Neuroimmunol 1999; 94: 212-221
    CrossrefPubMedGoogle Scholar
  • 56 Göbel K, Pankratz S, Asaridou CM. et al. Blood coagulation factor XII drives adaptive immunity during neuroinflammation via CD87-mediated modulation of dendritic cells. Nat Commun 2016; 7: 11626
    CrossrefPubMedGoogle Scholar
  • 57 Göbel K, Kraft P, Pankratz S. et al. Prothrombin and factor X are elevated in multiple sclerosis patients. Ann Neurol 2016; 80: 946-951
    CrossrefPubMedGoogle Scholar
  • 58 Pankratz S, Bittner S, Kehrel BE. et al. The inflammatory role of platelets: translational insights from experimental studies of autoimmune disorders. Int J Mol Sci 2016; 17: pii: E1723
    CrossrefPubMedGoogle Scholar
  • 59 Bellizzi MJ, Geathers JS, Allan KC. et al. Platelet-activating factor receptors mediate excitatory postsynaptic hippocampal injury in experimental autoimmune encephalomyelitis. J Neurosci 2016; 36: 1336-1346
    CrossrefPubMedGoogle Scholar
  • 60 Luchtman D, Gollan R, Ellwardt E. et al. In vivo and in vitro effects of multiple sclerosis immunomodulatory therapeutics on glutamatergic excitotoxicity. J Neurochem 2016; 136: 971-980
    CrossrefPubMedGoogle Scholar
  • 61 Gadjanski I, Boretius S, Williams SK. et al. Role of n-type voltage-dependent calcium channels in autoimmune optic neuritis. Ann Neurol 2009; 66: 81-93
    CrossrefPubMedGoogle Scholar
  • 62 Hoffmann DB, Williams SK, Bojcevski J. et al. Calcium influx and calpain activation mediate preclinical retinal neurodegeneration in autoimmune optic neuritis. J Neuropathol Exp Neurol 2013; 72: 745-757
    CrossrefPubMedGoogle Scholar
  • 63 Sühs KW, Fairless R, Williams SK. et al. N-methyl-D-aspartate receptor blockade is neuroprotective in experimental autoimmune optic neuritis. J Neuropathol Exp Neurol 2014; 73: 507-518
    CrossrefPubMedGoogle Scholar