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Mechanisms of Injury‐Induced Calcium Entry into Peripheral Nerve Myelinated Axons: Role of Reverse Sodium‐Calcium Exchange
Author(s) -
Lehning Ellen J.,
Doshi Renu,
Isaksson Norman,
Stys Peter K.,
LoPachin Richard M.
Publication year - 1996
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.1471-4159.1996.66020493.x
Subject(s) - bepridil , chemistry , calcium , axoplasm , biophysics , axon , nifedipine , tetrodotoxin , egta , depolarization , channel blocker , anatomy , verapamil , biology , organic chemistry
To investigate the route of axonal Ca 2+ entry during anoxia, electron probe x‐ray microanalysis was used to measure elemental composition of anoxic tibial nerve myelinated axons after in vitro experimental procedures that modify transaxolemmal Na + and Ca 2+ movements. Perfusion of nerve segments with zero‐Na + /Li + ‐substituted medium and Na + channel blockade by tetrodotoxin (1 µ M ) prevented anoxia‐induced increases in Na and Ca concentrations of axoplasm and mitochondria. Incubation with a zero‐Ca 2+ /EGTA perfusate impeded axonal and mitochondrial Ca accumulation during anoxia but did not affect characteristic Na and K responses. Inhibition of Na + ‐Ca 2+ exchange with bepridil (50 µ M ) reduced significantly the Ca content of anoxic axons although mitochondrial Ca remained at anoxic levels. Nifedipine (10 µ M ), an L‐type Ca 2+ channel blocker, did not alter anoxia‐induced changes in axonal Na, Ca, and K. Exposure of normoxic control nerves to tetrodotoxin, bepridil, or nifedipine did not affect axonal elemental composition, whereas both zero‐Ca 2+ and zero‐Na + solutions altered normal elemental content characteristically and significantly. The findings of this study suggest that during anoxia, Na + enters axons via voltage‐gated Na + channels and that subsequent increases in axoplasmic Na + are coupled functionally to extraaxonal Ca 2+ import. Intracellular Na + ‐dependent, extraaxonal Ca 2+ entry is consistent with reverse operation of the axolemmal Na + ‐Ca 2+ exchanger, and we suggest that this mode of Ca 2+ influx plays a general role in peripheral nerve axon injury.