STIM2 regulates capacitive Ca2+ entry in neurons and plays a key role in hypoxic neuronal cell death.
Excessive cytosolic calcium ion (Ca(2+)) accumulation during cerebral ischemia triggers neuronal cell death, but the underlying mechanisms are poorly understood. Capacitive Ca(2+) entry (CCE) is a process whereby depletion of intracellular Ca(2+) stores causes the activation of plasma membrane Ca(2+) channels. In nonexcitable cells, CCE is controlled by the endoplasmic reticulum (ER)-resident Ca(2+) sensor STIM1, whereas the closely related protein STIM2 has been proposed to regulate basal cytosolic and ER Ca(2+) concentrations and make only a minor contribution to CCE. Here, we show that STIM2, but not STIM1, is essential for CCE and ischemia-induced cytosolic Ca(2+) accumulation in neurons. Neurons from Stim2(-/-) mice showed significantly increased survival under hypoxic conditions compared to neurons from wild-type controls both in culture and in acute hippocampal slice preparations. In vivo, Stim2(-/-) mice were markedly protected from neurological damage in a model of focal cerebral ischemia. These results implicate CCE in ischemic neuronal cell death and establish STIM2 as a critical mediator of this process.
Berna-Erro
Alejandro
A
Rudolf Virchow Center, DFG Research Center for Experimental Biomedicine, University of Würzburg, Josef-Schneider-Strasse 2, D15 97080, Würzburg, Germany.
Braun
Attila
A
Kraft
Robert
R
Kleinschnitz
Christoph
C
Schuhmann
Michael K
MK
Stegner
David
D
Wultsch
Thomas
T
Eilers
Jens
J
Meuth
Sven G
SG
Stoll
Guido
G
Nieswandt
Bernhard
B
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D016923:Cell Death; D015687:Cell Hypoxia; D002478:Cells, Cultured; D005260:Female; D020925:Hypoxia-Ischemia, Brain / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology* / Q000378:metabolism*; D009928:Organ Specificity; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D000071738:Stromal Interaction Molecule 2; D046509:Tissue Culture Techniques
D008562:Membrane Glycoproteins; D020033:Protein Isoforms; C525024:Stim2 protein, mouse; D000071738:Stromal Interaction Molecule 2; D002118:Calcium