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The Journal of Neuroscience, March 15, 2001, 21(6):1893-1901

Mitochondria Control AMPA/Kainate Receptor-Induced Cytoplasmic Calcium Deregulation in Rat Cerebellar Granule Cells

A. Cristina Rego, Manus W. Ward, and David G. Nicholls

Buck Institute for Age Research, Novato, California 94945-1400

Although mitochondria mediate the delayed failure of cytoplasmic Ca²⁺ homeostasis [delayed Ca²⁺ deregulation (DCD)] in rat cerebellar granule cells resulting from chronic activation of NMDA receptors, their role in AMPA/KA-induced DCD remains to be established. The mitochondrial ATP synthase inhibitor oligomycin protected cells against KA- but not NMDA-evoked DCD. In contrast to NMDA-evoked DCD, no additional protection was afforded by the further addition of rotenone. The effects of KA on cytoplasmic Ca²⁺ homeostasis, including the protection afforded by oligomycin, could be reproduced by veratridine. KA exposure induced a partial mitochondrial depolarization that was enhanced by oligomycin, indicating ATP synthase reversal. The nonglycolytic substrates pyruvate and lactate were unable to maintain Ca²⁺ homeostasis in the presence of KA. In contrast to NMDA, KA exposure did not cause mitochondrial Ca²⁺ loading. The data indicate that Na⁺ entry via noninactivating AMPA/KA receptors or voltage-activated Na⁺ channels compromises mitochondrial function sufficiently to cause ATP synthase reversal. Oligomycin may protect by preventing the consequent mitochondrial drain of cytoplasmic ATP.

Key words: calcium; cerebellar granule cells; kainate; mitochondrial membrane potential; NMDA; glutamate excitotoxicity; glutamate receptors

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Copyright © 2001 Society for Neuroscience  0270-6474/01/2161893-09$05.00/0

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