Metabotropic Receptor-Mediated Ca Signaling Elevates Mitochondrial Ca and Stimulates Oxidative Metabolism in Hippocampal Slice Cultures

Kann, Oliver, Richard Kovács, and Uwe Heinemann. Metabotropic receptor-mediated Ca signaling elevates mitochondrial Ca and stimulates oxidative metabolism in hippocampal slice cultures. J Neurophysiol 90: 613–621, 2003. First published April 30, 2003; 10.1152/jn.00042.2003. Metabotropic receptors modulate numerous cellular processes by intracellular Ca signaling, but less is known about their role in regulating mitochondrial metabolic function within the CNS. In this study, we demonstrate in area CA3 of rat organotypic hippocampal slice cultures that glutamatergic, serotonergic, and muscarinic metabotropic receptor ligands, namely trans-azetidine-2,4dicarboxylic acid, -methyl-5-hydroxytryptamine, and carbachol, transiently increase mitochondrial Ca concentration ([Ca ]m) as recorded by changes in Rhod-2 fluorescence, stimulate mitochondrial oxidative metabolism as revealed by elevations in NAD(P)H fluorescence, and induce K outward currents as monitored by rapid increases in extracellular K concentration ([K ]o). Carbachol (1– 1,000 M) elevated NAD(P)H fluorescence by 14% F/F0 and increased [K ]o by 4.3 mM in a dose-dependent manner. Carbachol-induced responses persisted in Ca -free solution and blockade of ionotropic glutamatergic and nicotinic receptors. Under similar conditions caffeine, known to cause Ca -induced Ca release (CICR), also evoked elevations in [Ca ]m, NAD(P)H fluorescence and [K ]o that, in contrast to carbachol-induced responses, displayed oscillations. After depletion of intracellular Ca stores by carbachol in Ca -free solution, re-application of 1.6 mM Ca -containing solution triggered marked elevations in [Ca ]m, NAD(P)H fluorescence and [K ]o. These data indicate that metabotropic transmission effectively regulates mitochondrial oxidative metabolism via diverse receptor types in hippocampal cells and that inonitol 1,4,5-trisphosphate-induced Ca release (IICR) or CICR or capacitative Ca entry might suffice in stimulating oxidative metabolism by elevating [Ca ]m. Thus activation of metabotropic receptors might significantly contribute to generation of ATP within neurons and glial cells.