title: STIM1, STIM2, and Orai1 regulate store-operated calcium entry and purinergic activation of microglia.
abstract: Activation of microglia is the first and main immune response to brain injury. Release of the nucleotides ATP, ADP, and UDP from damaged cells regulate microglial migration and phagocytosis via purinergic P2Y receptors. We hypothesized that store-operated Ca(2+) entry (SOCE), the prevalent Ca(2+) influx mechanism in non-excitable cells, is a potent mediator of microglial responses to extracellular nucleotides. Expression analyses of STIM Ca(2+) sensors and Orai Ca(2+) channel subunits, that comprise the molecular machinery of SOCE, showed relevant levels of STIM1, STIM2, and Orai1 in cultured mouse microglia. STIM1 expression and SOCE were down-regulated by treatment of microglia with lipopolysaccharide, suggesting that inflammation limits SOCE by lower STIM1 abundance. Ca(2+) entry induced by cyclopiazonic acid, ATP, the P2Y6 receptor agonist UDP, or the P2Y12 receptor agonist 2-methylthio-ADP (2-MeSADP) was clearly affected in microglia from Stim1(-/-) , Stim2(-/-) , and Orai1(-/-) mice. SOCE blockers or ablation of STIM1, STIM2, or Orai1 severely impaired nucleotide-induced migration and phagocytosis in microglia. Thus, this study assigns SOCE, regulated by STIM1, STIM2, and Orai1 an essential role in purinergic signaling and activation of microglia.
authors.affiliation: Carl-Ludwig-Institute for Physiology, University of Leipzig, 04103, Leipzig, Germany.
authors.forename: Marlen
authors.initials: M
authors.lastname: Michaelis
authors.forename: Bernhard
authors.initials: B
authors.lastname: Nieswandt
authors.forename: David
authors.initials: D
authors.lastname: Stegner
authors.forename: Jens
authors.initials: J
authors.lastname: Eilers
authors.forename: Robert
authors.initials: R
authors.lastname: Kraft
mesh_terms: D000244:Adenosine Diphosphate / Q000031:analogs & derivatives / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D020013:Calcium Signaling / Q000276:immunology*; D018929:Cell Culture Techniques; D007211:Indoles / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017628:Microglia / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D000071740:ORAI1 Protein; D010587:Phagocytosis / Q000276:immunology; D000071737:Stromal Interaction Molecule 1; D000071738:Stromal Interaction Molecule 2; D013873:Thionucleotides / Q000378:metabolism; D014530:Uridine Diphosphate / Q000378:metabolism
chemical_list: D015220:Calcium Channels; D007211:Indoles; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D000071740:ORAI1 Protein; C520430:Orai1 protein, mouse; C100757:Stim1 protein, mouse; C525024:Stim2 protein, mouse; D000071737:Stromal Interaction Molecule 1; D000071738:Stromal Interaction Molecule 2; D013873:Thionucleotides; C082161:lipopolysaccharide A; C002480:methylthio-ADP; D014530:Uridine Diphosphate; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D002118:Calcium; C000543:cyclopiazonic acid
keywords: microglia; migration; phagocytosis; store-operated calcium entry