title: CGP37157 modulates mitochondrial Ca2+ homeostasis in cultured rat dorsal root ganglion neurons.
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.
authors.affiliation: Department of Pharmacology, University of Minnesota Medical School, Minneapolis 55455, USA.
authors.forename: K T
authors.initials: KT
authors.lastname: Baron
authors.forename: S A
authors.initials: SA
authors.lastname: Thayer
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D002998:Clonazepam / Q000031:analogs & derivatives* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005456:Fluorescent Dyes; D005727:Ganglia, Spinal / Q000166:cytology / Q000378:metabolism*; D006706:Homeostasis / Q000187:drug effects*; D007211:Indoles; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors*; D013841:Thiazepines / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D005456:Fluorescent Dyes; D007211:Indoles; D019831:Sodium-Calcium Exchanger; D013841:Thiazepines; D002998:Clonazepam; C079032:CGP 37157; C048960:indo-1; D002118:Calcium