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

Alejandro Berna-Erro^1,2*, Attila Braun^1,2*, Robert Kraft³, Christoph Kleinschnitz⁴, Michael K. Schuhmann⁴, David Stegner^1,2, Thomas Wultsch⁵, Jens Eilers³, Sven G. Meuth⁴, Guido Stoll⁴, and Bernhard Nieswandt^1,2

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.

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.

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

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