Cited by 81Mitochondrial Function and PathologyNeuroscience and Neuropharmacology ResearchIon channel regulation and function

Comparative Impact of Voltage-Gated Calcium Channels and NMDA Receptors on Mitochondria-Mediated Neuronal Injury

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Stanika, Ruslan I., Villanueva, Idalis, Kazanina, Galina, Andrews, S. Brian, Pivovarova, Natalia B.·2012·The Journal of Neuroscience

Abstract

Glutamate excitotoxicity, a major component of many neurodegenerative disorders, is characterized by excessive calcium influx selectively through NMDARs. However, there is a substantial uncertainty concerning why other known routes of significant calcium entry, in particular, VGCCs, are not similarly toxic. Here, we report that in the majority of neurons in rat hippocampal and cortical cultures, maximal L-type VGCC activation induces much lower calcium loading than toxic NMDAR activation. Consequently, few depolarization-activated neurons exhibit calcium deregulation and cell death. Activation of alternative routes of calcium entry induced neuronal death in proportion to the degree of calcium loading. In a small subset of neurons, depolarization evoked stronger calcium elevations, approaching those induced by toxic NMDA. These neurons were characterized by elevated expression of VGCCs and enhanced voltage-gated calcium currents, mitochondrial dysfunction and cell death. Preventing VGCC-dependent mitochondrial calcium loading resulted in stronger cytoplasmic calcium elevations, whereas inhibiting mitochondrial calcium clearance accelerated mitochondrial depolarization. Both observations further implicate mitochondrial dysfunction in VGCC-mediated cell death. Results indicate that neuronal vulnerability tracks the extent of calcium loading but does not appear to depend explicitly on the route of calcium entry.

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Crossref · 10.1523/jneurosci.6008-11.2012

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  • Excessive or prolonged activation of CaV channels leads to calcium overload in mitochondria, disrupting their normal function.

    “excessive or prolonged activation of CaV channels leads to calcium overload in mitochondria, disrupting their normal function at multiple levels and significantly impacting cellular development and homeostasis101,102.”

    From CYFIP1 governs the development of cortical axons by modulating calcium availability (2025) · cites this paper as [101]

    The Results (‘VGCC-mediated calcium loading and mitochondrial dysfunction,’ Figs. 3–5) show that VGCC-mediated calcium entry can cause mitochondrial overload and damage, but this occurred in a minor subset of neurons; most showed little mitochondrial calcium accumulation or dysfunction. The cited passages do not establish an effect of prolonged activation or the sentence’s broader claim about cellular development and homeostasis. (LLM, conf=0.88)

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Authors
Stanika, R. I., Villanueva, I., Kazanina, G., Andrews, S. B., & Pivovarova, N. B.
Affiliations
National Institutes of Health (US)
Corresponding author
Pivovarova, Natalia B.
Venue
The Journal of Neuroscience
Published
2012-05-09
Volume
32
Issue
19
Pages
6642-6650
ISSN
  • 0270-6474 (ISSN-L)
  • 1529-2401
OpenAlex
W1988198142
Cited by
81
References
44
Citations by year
2026: 2 · 2025: 5 · 2024: 2 · 2023: 7 · 2022: 6 · 2021: 9 · 2020: 6 · 2019: 4 · 2018: 7 · 2017: 5 · 2016: 2 · 2015: 4 · 2014: 9 · 2013: 13
FWCI
3.35
Type
journal article
Language
en
Open access
Locations
  • Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health
  • National Institute of Neurological Disorders and Stroke (ZIANS002610)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
Keywords
voltage-gated calcium channels, L-type calcium channels, NMDA receptor, glutamate excitotoxicity, mitochondrial calcium uptake, mitochondrial depolarization, neuronal cell death, calcium influx, hippocampal neurons, cortical neurons, neurodegeneration
MeSH terms
Animals, Calcium, Cells, Cultured, Mitochondria, Neurons, Calcium Channels, Receptors, N-Methyl-D-Aspartate, Cell Death, Rats, Sprague-Dawley, Rats

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