Cleavage of the plasma membrane Na+/Ca2+ exchanger in excitotoxicity

• Published in: Cell Vol. 120; no. 2; pp. 275 - 285
• Main Authors: Bano, Daniele, Young, Kenneth W, Guerin, Christopher J, Lefeuvre, Ros, Rothwell, Nancy J, Naldini, Luigi, Rizzuto, Rosario, Carafoli, Ernesto, Nicotera, Pierluigi
• Format: Journal Article
• Language: English
• Published: United States 28-01-2005
• Subjects: Amino Acid Sequence; Animals; Brain Ischemia - physiopathology; Calcium - metabolism; Calcium-Binding Proteins - pharmacology; Calpain - antagonists & inhibitors; Calpain - metabolism; Cell Death - drug effects; Cell Death - physiology; Cell Membrane - drug effects; Cell Membrane - physiology; Cells, Cultured; Cysteine Proteinase Inhibitors - pharmacology; Ion Channel Gating - drug effects; Ion Channel Gating - physiology; Membrane Transport Proteins - metabolism; Molecular Sequence Data; Neurons - enzymology; Neurons - physiology; Rats; Rats, Wistar; Receptors, Glutamate - metabolism; Sodium-Calcium Exchanger - metabolism
• ISSN: 0092-8674
• DOI: 10.1016/j.cell.2004.11.049

In brain ischemia, gating of postsynaptic glutamate receptors and other membrane channels triggers intracellular Ca2+ overload and cell death. In excitotoxic settings, the initial Ca2+ influx through glutamate receptors is followed by a second uncontrolled Ca2+ increase that leads to neuronal demise. Here we report that the major plasma membrane Ca2+ extruding system, the Na+/Ca2+ exchanger (NCX), is cleaved during brain ischemia and in neurons undergoing excitotoxicity. Inhibition of Ca2+-activated proteases (calpains) by overexpressing their endogenous inhibitor protein, calpastatin or the expression of an NCX isoform not cleaved by calpains, prevented Ca2+ overload and rescued neurons from excitotoxic death. Conversely, down-regulation of NCX by siRNA compromised neuronal Ca2+ handling, transforming the Ca2+ transient elicited by non-excitotoxic glutamate concentrations into a lethal Ca2+overload. Thus, proteolytic inactivation of NCX-driven neuronal Ca2+ extrusion is responsible for the delayed excitotoxic Ca2+ deregulation and neuronal death.