Depolarization-induced Ca2+ release in ischemic spinal cord white matter involves L-type Ca2+ channel activation of ryanodine receptors.
The mechanisms of Ca(2+) release from intracellular stores in CNS white matter remain undefined. In rat dorsal columns, electrophysiological recordings showed that in vitro ischemia caused severe injury, which persisted after removal of extracellular Ca(2+); Ca(2+) imaging confirmed that an axoplasmic Ca(2+) rise persisted in Ca(2+)-free perfusate. However, depletion of Ca(2+) stores or reduction of ischemic depolarization (low Na(+), TTX) were protective, but only in Ca(2+)-free bath. Ryanodine or blockers of L-type Ca(2+) channel voltage sensors (nimodipine, diltiazem, but not Cd(2+)) were also protective in zero Ca(2+), but their effects were not additive with ryanodine. Immunoprecipitation revealed an association between L-type Ca(2+) channels and RyRs, and immunohistochemistry confirmed colocalization of Ca(2+) channels and RyR clusters on axons. Similar to "excitation-contraction coupling" in skeletal muscle, these results indicate a functional coupling whereby depolarization sensed by L-type Ca(2+) channels activates RyRs, thus releasing damaging amounts of Ca(2+) under pathological conditions in white matter.
Ouardouz
Mohamed
M
Ottawa Health Research Institute, Division of Neuroscience, University of Ottawa, Ottawa, Ontario K1Y 4K9, Canada.
Nikolaeva
Maria A
MA
Coderre
Elaine
E
Zamponi
Gerald W
GW
McRory
John E
JE
Trapp
Bruce D
BD
Yin
Xinghua
X
Wang
Weili
W
Woulfe
John
J
Stys
Peter K
PK
D000200:Action Potentials / Q000502:physiology*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D015687:Cell Hypoxia / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D020671:Posterior Horn Cells / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D051381:Rats; D020318:Rats, Long-Evans; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure
D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D019837:Ryanodine Receptor Calcium Release Channel; D002118:Calcium