Preferential Zn 2+ influx through Ca 2+ -permeable AMPA/kainate channels triggers prolonged mitochondrial superoxide production
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Synaptically released Zn 2+ can enter and cause injury to postsynaptic neurons. Microfluorimetric studies using the Zn 2+ -sensitive probe, Newport green, examined levels of [Zn 2+ ] i attained in cultured cortical neurons on exposure to N- methyl- d -asparte, kainate, or high K + (to activate voltage-sensitive Ca 2+ channels) in the presence of 300 μM Zn 2+ . Indicating particularly high permeability through Ca 2+ -permeable α-amino3-hydroxy-5-methyl-4-isoxazolepropionic-acid/kainate (Ca-A/K) channels, micromolar [Zn 2+ ] i rises were observed only after kainate exposures and only in neurons expressing these channels [Ca-A/K(+) neurons]. Further studies using the oxidation-sensitive dye, hydroethidine, revealed Zn 2+ -dependent reactive oxygen species (ROS) generation that paralleled the [Zn 2+ ] i rises, with rapid oxidation observed only in the case of Zn 2+ entry through Ca-A/K channels. Indicating a mitochondrial source of this ROS generation, hydroethidine oxidation was inhibited by the mitochondrial electron transport blocker, rotenone. Additional evidence for a direct interaction between Zn 2+ and mitochondria was provided by the observation that the Zn 2+ entry through Ca-A/K channels triggered rapid mitochondrial depolarization, as assessed by using the potential-sensitive dye tetramethylrhodamine ethylester. Whereas Ca 2+ influx through Ca-A/K channels also triggers ROS production, the [Zn 2+ ] i rises and subsequent ROS production are of more prolonged duration.
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Unlike calcium, zinc influx through calcium-permeable AMPA receptors can cause long-lasting superoxide production in mitochondria.
“Unlike Ca 2+ , the influx of zinc through Ca 2+ -permeable AMPA receptors can lead to a longlasting production of superoxide in mitochondria [112].”
From Parvalbumin interneuron vulnerability and brain disorders (2021) · cites this paper as [112]
Calcium-permeable AMPA receptors are a major entry point for zinc.
“Ca 2+ -permeable AMPA receptors are a major entry point of zinc [111-113].”
From Parvalbumin interneuron vulnerability and brain disorders (2021) · cites this paper as [112]
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Self-citation
- Authors
- Sensi, S. L., Yin, H. Z., Carriedo, S. G., Rao, S. S., & Weiss, J. H.
- Affiliations
- University of California, Irvine (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 1999-03-02
- Volume
- 96
- Issue
- 5
- Pages
- 2414-2419
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC26798
- OpenAlex
- W2082469108
- Cited by
- 408
- References
- 49
- Citations by year
- 2026: 6 · 2025: 6 · 2024: 8 · 2023: 6 · 2022: 10 · 2021: 11 · 2020: 13 · 2019: 7 · 2018: 10 · 2017: 7 · 2016: 7 · 2015: 14 · 2014: 16 · 2013: 13 · 2012: 20
- FWCI
- 9.16
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- ALS Association
- National Institutes of Health (5r01ns030884-11, NS30884, AG00096)
- National Institute on Aging (AG00096-15, T32AG000096)
- National Human Genome Research Institute (F31HG000179, HG00179)
- National Institute of Neurological Disorders and Stroke (NS 30884)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Nursing › Nutrition and Dietetics › Trace Elements in Health
- Keywords
- zinc influx, mitochondrial superoxide production, reactive oxygen species, NMDA, kainic acid, cortical neurons, rotenone
- MeSH terms
- Calcium, Cells, Cultured, Embryo, Mammalian, Embryo, Nonmammalian, Kainic Acid, Membrane Potentials, Mitochondria, Neurons, Neurotoxins, Potassium, Superoxides, Zinc, Calcium Channels, Receptors, N-Methyl-D-Aspartate, N-Methylaspartate, Receptors, AMPA, Kainic Acid Receptors, Neocortex
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