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Sci. Signal., 20 October 2009
Vol. 2, Issue 93, p. ra67
[DOI: 10.1126/scisignal.2000522]

RESEARCH ARTICLES

STIM2 Regulates Capacitive Ca2+ Entry in Neurons and Plays a Key Role in Hypoxic Neuronal Cell Death

Alejandro Berna-Erro1,2*, Attila Braun1,2*, Robert Kraft3, Christoph Kleinschnitz4, Michael K. Schuhmann4, David Stegner1,2, Thomas Wultsch5, Jens Eilers3, Sven G. Meuth4, Guido Stoll4, and Bernhard Nieswandt1,2{dagger}

1 Rudolf Virchow Center, DFG Research Center for Experimental Biomedicine, University of Würzburg, Josef-Schneider-Straße 2, D15 97080, Würzburg, Germany.
2 Vascular Medicine, University of Würzburg, Josef-Schneider-Straße 2, D15 97080, Würzburg, Germany.
3 Carl-Ludwig-Institute for Physiology, University of Leipzig, Liebigstr. 27, 04103, Leipzig, Germany.
4 Department of Neurology, University Clinic Würzburg, Josef-Schneider-Str. 11, 97080, Würzburg, Germany.
5 Molecular and Clinical Psychobiology, Department of Psychiatry and Psychotherapy, University of Würzburg, Fuechsleinstr. 15, 97080, Würzburg, Germany.

* These authors contributed equally to this work.

Abstract: Excessive cytosolic calcium ion (Ca2+) accumulation during cerebral ischemia triggers neuronal cell death, but the underlying mechanisms are poorly understood. Capacitive Ca2+ entry (CCE) is a process whereby depletion of intracellular Ca2+ stores causes the activation of plasma membrane Ca2+ channels. In nonexcitable cells, CCE is controlled by the endoplasmic reticulum (ER)–resident Ca2+ sensor STIM1, whereas the closely related protein STIM2 has been proposed to regulate basal cytosolic and ER Ca2+ 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 Ca2+ 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.

{dagger} To whom correspondence should be addressed. E-mail: bernhard.nieswandt{at}virchow.uni-wuerzburg.de

Citation: A. Berna-Erro, A. Braun, R. Kraft, C. Kleinschnitz, M. K. Schuhmann, D. Stegner, T. Wultsch, J. Eilers, S. G. Meuth, G. Stoll, B. Nieswandt, STIM2 Regulates Capacitive Ca2+ Entry in Neurons and Plays a Key Role in Hypoxic Neuronal Cell Death. Sci. Signal. 2, ra67 (2009).

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