L-type Ca2+ channel–mediated Ca2+ influx adjusts neuronal mitochondrial function to physiological and pathophysiological conditions

Hotka, Matej and Cagalinec, Michal and Hilber, Karlheinz and Hool, Livia and Boehm, Stefan and Kubista, Helmut (2020) L-type Ca2+ channel–mediated Ca2+ influx adjusts neuronal mitochondrial function to physiological and pathophysiological conditions. Science Signaling, 13 (618). pp. eaaw6923. ISSN 1945-0877

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Link to published document: http://doi.org/10.1126/scisignal.aaw6923


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.

Item Type: Article
Subjects: R Medicine > R Medicine (General)
Depositing User: Repository Administrator
Date Deposited: 17 Feb 2020 21:08
Last Modified: 14 Oct 2021 07:43
URI: http://eprints.victorchang.edu.au/id/eprint/931

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