Cleavage of the Plasma Membrane Na+/Ca2+ Exchanger in Excitotoxicity (original) (raw)

elicited by non-excitotoxic glutamate concentrations into a lethal Ca 2؉ overload. Thus, proteolytic inactiva-and Pierluigi Nicotera 1, * 1 MRC Toxicology Unit tion of NCX-driven neuronal Ca 2؉ extrusion is responsible for the delayed excitotoxic Ca 2؉ deregulation and University of Leicester Hodgkin Building neuronal death. Lancaster Road LE1 9HN Leicester Introduction United Kingdom 2 Department of Cell Physiology and Pharmacology Excitotoxicity (Olney, 1969) plays a central role in neu-University of Leicester ronal demise during brain ischemia. Prolonged oversti-Maurice Shock Medical Sciences Building mulation of the glutamate N-methyl-D-aspartate (NMDA) University Road LE1 9HN receptor subtype leads to Ca 2ϩ and Na ϩ overload in Leicester postsynaptic neurons (Choi, 1988; Lipton and Rosen-United Kingdom berg, 1994; Rothman and Olney, 1995). In cultured neu-3 School of Biological Sciences rons, and also in stroke models, the initial Ca 2ϩ influx University of Manchester triggered by glutamate through NMDA-Rs is followed by Manchester M13 9PT a delayed massive Ca 2ϩ accumulation, which invariably United Kingdom results in cell death (Budd and Nicholls, 1996; Rothman 4 San Raffaele Telethon Institute for Gene Therapy et al., 1987). The amplitude of the initial Ca 2ϩ increase Via Olgettina 58 mediated by glutamate is within the range of nonlethal 20132 Milano stimulations, whereas the delayed intracellular Ca 2ϩ rise 5 Section of General Pathology is sustained and apparently beyond rectification, sug-Department of Experimental and Diagnostic gesting that additional mechanisms are involved to ter-Medicine minally deregulate cellular Ca 2ϩ handling. The mecha-Via Borsari 46 nisms responsible for the delayed Ca 2ϩ increase that 44100 Ferrara precedes neuronal demise remain unclear. Italy Ca 2ϩ inflow through voltage-dependent or indepen-6 Department of Biochemistry dent channels can lead to neuronal Ca 2ϩ overload under University of Padova excitotoxic (Fryer et al., 1999), anoxic (Aarts et al., 2003), Viale G. Colombo 3 or ischemic (Xiong et al., 2004) conditions. In addition, 35121 Padova mitochondria Ca 2ϩ accumulation and its subsequent re-Italy lease may play an important role in maintaining a Ca 2ϩ 7 Venetian Institute of Molecular Medicine (VIMM) overload (Schinder et al. 1996). It is also well established Via Orus 2 that mitochondrial dysfunction is involved in excitotoxic 35129 Padova demise (Ankarcrona et al., 1995; Reynolds, 1999; Ward Italy et al., 2000). Nevertheless, the combination of increased Ca 2ϩ influx into neurons and mitochondrial Ca 2ϩ release may not fully account for the irreversible buildup of intracellu-Summary lar Ca 2ϩ after excitotoxic stimulation. Conceivably, the delayed increase in cellular Ca 2ϩ should be rectified by In brain ischemia, gating of postsynaptic glutamate the mechanisms operating cellular Ca 2ϩ extrusion. In receptors and other membrane channels triggers inneurons, Ca 2ϩ extrusion is operated by the plasma memtracellular Ca 2؉ overload and cell death. In excitotoxic brane Ca 2ϩ pump (PMCA) and by Na ϩ /Ca 2ϩ exchangers settings, the initial Ca 2؉ influx through glutamate re-(NCX). PMCA has high Ca 2ϩ affinity but low transport ceptors is followed by a second uncontrolled Ca 2؉ incapacity, whereas NCX has a low affinity, but a higher crease that leads to neuronal demise. Here we report capacity to transport Ca 2ϩ (Carafoli et al., 2001). Inhibithat the major plasma membrane Ca 2؉ extruding systion of Ca 2ϩ efflux from cells is sufficient to cause a tem, the Na ؉ /Ca 2؉ exchanger (NCX), is cleaved during sustained intracellular Ca 2ϩ elevation and the demise of brain ischemia and in neurons undergoing excitotoxinonneuronal cells by activating Ca 2ϩ-dependent hycity. Inhibition of Ca 2؉-activated proteases (calpains) drolytic enzymes including members of the calpain proby overexpressing their endogenous inhibitor protein, tease family (Nicotera et al., 1986). calpastatin or the expression of an NCX isoform not Calpains (Mellgren et al., 1989; Murachi et al., 1987) cleaved by calpains, prevented Ca 2؉ overload and resmodulate a variety of physiological processes (Robles et al., 2003) but can also become important mediators of cell death (Neumar et al., 2003).