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A reversal to limit neuronal death
Ca2+ ions are an important second messenger, but excessive Ca2+ mitochondrial influx from the cytoplasm can trigger cell death. In response to depolarizing stimuli, L-type Ca2+ channels mediate Ca2+ entry into neurons. Hotka et al. found that the effect of L-type Ca2+ channel activity on mitochondrial Ca2+ concentrations depended on the strength of the depolarizing stimulus applied to neurons. Stimuli of moderate strength enhanced the production of ATP by ATP synthase. In contrast, stronger depolarizing stimuli caused the ATP synthase to operate in reverse mode and consume ATP, which helped to limit increases in mitochondrial Ca2+. These results may explain why neuroprotection is seen not only with blockers of L-type Ca2+ channel activity but also with compounds that stimulate channel activity.
Abstract
L-type voltage-gated Ca2+ channels (LTCCs) are implicated in neurodegenerative processes and cell death. Accordingly, LTCC antagonists have been proposed to be neuroprotective, although this view is disputed, because intentional LTCC activation can also have beneficial effects. LTCC-mediated Ca2+ influx influences mitochondrial function, which plays a crucial role in the regulation of cell viability. Hence, we investigated the effect of modulating LTCC-mediated Ca2+ influx on mitochondrial function in cultured hippocampal neurons. To activate LTCCs, neuronal activity was stimulated by increasing extracellular K+ or by application of the GABAA receptor antagonist bicuculline. The activity of LTCCs was altered by application of an agonistic (Bay K8644) or an antagonistic (isradipine) dihydropyridine. Our results demonstrated that activation of LTCC-mediated Ca2+ influx affected mitochondrial function in a bimodal manner. At moderate stimulation strength, ATP synthase activity was enhanced, an effect that involved Ca2+-induced Ca2+ release from intracellular stores. In contrast, high LTCC-mediated Ca2+ loads led to a switch in ATP synthase activity to reverse-mode operation. This effect, which required nitric oxide, helped to prevent mitochondrial depolarization and sustained increases in mitochondrial Ca2+. Our findings indicate a complex role of LTCC-mediated Ca2+ influx in the tuning and maintenance of mitochondrial function. Therefore, the use of LTCC inhibitors to protect neurons from neurodegeneration should be reconsidered carefully.
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