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In depolarized and glucose‐deprived neurons, Na + influx reverses plasmalemmal K + ‐dependent and K + ‐independent Na + /Ca 2+ exchangers and contributes to NMDA excitotoxicity
Author(s) -
Czyż Aneta,
Kiedrowski Lech
Publication year - 2002
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.2002.01227.x
Subject(s) - chemistry , gramicidin , ouabain , excitotoxicity , depolarization , biophysics , ionophore , cytosol , membrane potential , biochemistry , sodium , nmda receptor , membrane , enzyme , biology , receptor , organic chemistry
Cerebellar granule cells (CGCs) express K + ‐dependent (NCKX) and K + ‐independent (NCX) plasmalemmal Na + /Ca 2+ exchangers which, under plasma membrane‐depolarizing conditions and high cytosolic [Na + ], may reverse and mediate potentially toxic Ca 2+ influx. To examine this possibility, we inhibited NCX or NCKX with KB‐R7943 or K + ‐free medium, respectively, and studied how gramicidin affects cytosolic [Ca 2+ ] and 45 Ca 2+ accumulation. Gramicidin forms pores permeable to alkali cations but not Ca 2+ . Therefore, gramicidin‐induced Ca 2+ influx is indirect; it results from fluxes of monovalent cations. In the presence of Na + , but not Li + or Cs + , gramicidin induced Ca 2+ influx that was inhibited by simultaneous application of KB‐R7943 and K + ‐free medium. The data indicate that gramicidin‐induced Na + influx reverses NCX and NCKX. To test the role of NCX and/or NCKX in excitotoxicity, we studied how NMDA affects the viability of glucose‐deprived and depolarized CGCs. To assure depolarization of the plasma membrane, we inhibited Na + ,K + ‐ATPase with ouabain. Although inhibition of NCX or NCKX reversal failed to significantly limit 45 Ca 2+ accumulation and excitotoxicity, simultaneously inhibiting NCX and NCKX reversal was neuroprotective and significantly decreased NMDA‐induced 45 Ca 2+ accumulation. Our data suggest that NMDA‐induced Na + influx reverses NCX and NCKX and leads to the death of depolarized and glucose‐deprived neurons.