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Metabotropic Receptor-Mediated Ca²⁺ Signaling Elevates Mitochondrial Ca²⁺ and Stimulates Oxidative Metabolism in Hippocampal Slice Cultures

¹ Department of Neurophysiology, Charité, Humboldt University, D-10117 Berlin, Germany; ² Department of Neurochemistry, Hungarian Academy of Sciences, Budapest 1025, Hungary

Submitted 15 January 2003; accepted in final form 17 April 2003

Metabotropic receptors modulate numerous cellular processes by intracellular Ca²⁺ 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-2,4-dicarboxylic acid, -methyl-5-hydroxytryptamine, and carbachol, transiently increase mitochondrial Ca²⁺ concentration ([Ca²⁺]_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 µM) 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 Ca²⁺-free solution and blockade of ionotropic glutamatergic and nicotinic receptors. Under similar conditions caffeine, known to cause Ca²⁺-induced Ca²⁺ release (CICR), also evoked elevations in [Ca²⁺]_m, NAD(P)H fluorescence and [K⁺]_o that, in contrast to carbachol-induced responses, displayed oscillations. After depletion of intracellular Ca²⁺ stores by carbachol in Ca²⁺-free solution, re-application of 1.6 mM Ca²⁺-containing solution triggered marked elevations in [Ca²⁺]_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 Ca²⁺ release (IICR) or CICR or capacitative Ca²⁺ entry might suffice in stimulating oxidative metabolism by elevating [Ca²⁺]_m. Thus activation of metabotropic receptors might significantly contribute to generation of ATP within neurons and glial cells.

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