CGP37157 modulates mitochondrial Ca2+ homeostasis in cultured rat dorsal root ganglion neurons

European Journal of Pharmacology
Kyle T Baron, Stanley A Thayer

Abstract

The effects of 7-chloro-3,5-dihydro-5-phenyl-1H-4,1-benzothiazepine-2-on (CGP37157), an inhibitor of mitochondrial Na+/Ca2+ exchange, on depolarization-induced intracellular free Ca2+ concentration ([Ca2+]i) transients were studied in cultured rat dorsal root ganglion neurons with indo-1-based microfluorimetry. A characteristic plateau in the recovery phase of the [Ca2+]i transient resulted from mitochondrion-mediated [Ca2+]i buffering. It was blocked by metabolic poisons and was not dependent on extracellular Ca2+. CGP37157 produced a concentration-dependent decrease in the amplitude of the mitochondrion-mediated plateau phase (IC50 = 4 +/- 1 microM). This decrease in [Ca2+]i was followed by an increase in [Ca2+]i upon removal of the drug, suggesting that Ca2+ trapped in the matrix was released when the CGP37157 was removed from the bath. CGP37157 also inhibited depolarization-induced Ca2+ influx at the concentrations required to see effects on [Ca2+]i buffering. Thus, CGP37157 inhibits mitochondrial Na+/Ca2+ exchange and directly inhibits voltage-gated Ca2+ channels, suggesting caution in its use to study [Ca2+]i regulation in intact cells.

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