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

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