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

Cell. 2005 Jan 28;120(2):275-85. 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*


  • Calcium-Binding Proteins
  • Cysteine Proteinase Inhibitors
  • Membrane Transport Proteins
  • Receptors, Glutamate
  • Slc8a3 protein, rat
  • Sodium-Calcium Exchanger
  • calpastatin
  • Calpain
  • Calcium