Ac. Rego et al., Mitochondria control AMPA/kainate receptor-induced cytoplasmic calcium deregulation in rat cerebellar granule cells, J NEUROSC, 21(6), 2001, pp. 1893-1901
Although mitochondria mediate the delayed failure of cytoplasmic Ca2+ homeo
stasis [delayed Ca2+ deregulation (DCD)] in rat cerebellar granule cells re
sulting from chronic activation of NMDA receptors, their role in AMPA/KA-in
duced DCD remains to be established. The mitochondrial ATP synthase inhibit
or oligomycin protected cells against KA- but not NMDA-evoked DCD. In contr
ast to NMDA-evoked DCD, no additional protection was afforded by the furthe
r addition of rotenone. The effects of KA on cytoplasmic Ca2+ homeostasis,
including the protection afforded by oligomycin, could be reproduced by ver
atridine. KA exposure induced a partial mitochondrial depolarization that w
as enhanced by oligomycin, indicating ATP synthase reversal. The nonglycoly
tic substrates pyruvate and lactate were unable to maintain Ca2+ homeostasi
s in the presence of KA. In contrast to NMDA, KA exposure did not cause mit
ochondrial Ca2+ loading. The data indicate that Na+ entry via noninactivati
ng AMPA/KA receptors or voltage-activated Na+ channels compromises mitochon
drial function sufficiently to cause ATP synthase reversal. Oligomycin may
protect by preventing the consequent mitochondrial drain of cytoplasmic ATP
.