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L-type Ca 2+ channel–mediated Ca 2+ influx adjusts neuronal mitochondrial function to physiological and pathophysiological conditions
- Source :
- Sci Signal
- Publication Year :
- 2020
- Publisher :
- American Association for the Advancement of Science (AAAS), 2020.
-
Abstract
- L-type voltage-gated Ca(2+) 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 Ca(2+) influx influences mitochondrial function, which plays a crucial role in the regulation of cell viability. Hence, we investigated the effect of modulating LTCC-mediated Ca(2+) influx on mitochondrial function in cultured hippocampal neurons. To activate LTCCs, neuronal activity was stimulated by increasing extracellular K(+) or by application of the GABA(A) 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 Ca(2+) influx affected mitochondrial function in a bimodal manner. At moderate stimulation strength, ATP synthase activity was enhanced, an effect that involved Ca(2+)-induced Ca(2+)-release from intracellular stores. In contrast, high LTCC-mediated Ca(2+) 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 Ca(2+). Our findings indicate a complex role of LTCC-mediated Ca(2+) influx in the tuning and maintenance of mitochondrial function. Therefore, the use of LTCC inhibitors to protect neurons from neurodegeneration should be reconsidered carefully.
- Subjects :
- Calcium Channels, L-Type
Cell Survival
Hippocampus
Biochemistry
Neuroprotection
Article
Rats, Sprague-Dawley
medicine
Animals
Premovement neuronal activity
Calcium Signaling
Molecular Biology
Cells, Cultured
Neurons
Voltage-dependent calcium channel
GABAA receptor
Chemistry
Neurodegeneration
Biological Transport
Depolarization
Cell Biology
3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester
Bicuculline
Calcium Channel Blockers
medicine.disease
Mitochondria
Cell biology
Calcium Channel Agonists
Calcium
Isradipine
Intracellular
medicine.drug
Subjects
Details
- ISSN :
- 19379145 and 19450877
- Volume :
- 13
- Database :
- OpenAIRE
- Journal :
- Science Signaling
- Accession number :
- edsair.doi.dedup.....b672d788f69d763271006189f128e717