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Mol Pharmacol. 1995 Jan;47(1):140-7.

Glutamate-induced destabilization of intracellular calcium concentration homeostasis in cultured cerebellar granule cells: role of mitochondria in calcium buffering.

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  • 1Center for Neuropharmacology, Nathan S. Kline Institute for Psychiatric Research, New York University, Orangeburg 10962.

Abstract

The exposure of cultured cerebellar granule cells for 4 min to glutamate (50 microM) in a Mg2+-free medium containing 10 microM glycine elicited a prompt increase of the intracellular Ca2+ concentration ([Ca2+]i) to 5 microM, which was followed by a decline to 1.5 microM (as measured using fura-2); both events occurred while the glutamate pulse increased the intracellular sodium concentration ([Na+]i) to an estimated 60-100 mM. Because under these circumstances the plasma membrane Na+/Ca2+ exchanger cannot extrude Ca2+, other mechanisms should operate in causing the [Ca2+]i decline. To evaluate a possible role of intracellular Ca2+ stores in Ca2+ buffering, thapsigargin, ryanodine, and dantrolene were tested. Thapsigargin (1 microM) and ryanodine (10 microM) failed to modify the glutamate-elicited [Ca2+]i transients; results with dantrolene could not be considered because this drug by itself affected the fura-2 fluorescence. In contrast, carbonyl cyanide m-chlorophenylhydrazone (1 microM) and antimycin A1 (1 microM), which dissipate mitochondrial membrane potential by different mechanisms, virtually abolished the [Ca2+]i decline occurring either during glutamate application or after its removal. Moreover, when the residual [Na+]i increase persisting after glutamate removal was artificially abated, the Ca2+-buffering capacity of neurons was significantly improved. These data suggest that most of the Ca2+ entering the neurons during excitotoxic glutamate exposure is diverted to mitochondria and that the glutamate-induced increase of [Na+]i limits this mitochondrial Ca2+-buffering capacity, presumably via activation of the mitochondrial Na+/Ca2+ exchanger.

PMID:
7838122
[PubMed - indexed for MEDLINE]
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