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