Cleavage of the Plasma Membrane Na^+/Ca^2+ Exchanger in Excitotoxicity

In brain ischemia, gating of postsynaptic glutamate receptors and other membrane channels triggers intracellular Ca^2+ overload and cell death. In excitotoxic settings, the initial Ca^2+ influx through glutamate receptors is followed by a second uncontrolled Ca^2+ increase that leads to neuronal demise. Here we report that the major plasma membrane Ca^2+ extruding system, the Na^+/Ca^2+ exchanger (NCX), is cleaved during brain ischemia and in neurons undergoing excitotoxicity. Inhibition of Ca^2+-activated proteases (calpains) by overexpressing their endogenous inhibitor protein, calpastatin or the expression of an NCX isoform not cleaved by calpains, prevented Ca^2+ overload and rescued neurons from excitotoxic death. Conversely, down-regulation of NCX by siRNA compromised neuronal Ca^2+ handling, transforming the Ca^2+ transient elicited by non-excitotoxic glutamate concentrations into a lethal Ca^2+overload. Thus, proteolytic inactivation of NCX-driven neuronal Ca^2+ extrusion is responsible for the delayed excitotoxic Ca^2+ deregulation and neuronal death.