Calcium-permeable AMPA channels in neurodegenerative disease and ischemia
Abstract
Compelling evidence supports contributions of glutamate receptor overactivation ('excitotoxicity') to neurodegeneration in both acute conditions, such as stroke, and chronic neurodegenerative conditions, such as amyotrophic lateral sclerosis. However, anti-excitotoxic therapeutic trials, which have generally targeted highly Ca2+ permeable NMDA-type glutamate channels, have to date failed to demonstrate impressive efficacy. Whereas most AMPA type glutamate channels are Ca2+ impermeable, an evolving body of evidence supports the contention that relatively unusual Ca2+ permeable AMPA channels might be crucial contributors to injury in these conditions. These channels are preferentially expressed in discrete neuronal subpopulations, and their numbers appear to be upregulated in amyotrophic lateral sclerosis and stroke. In addition, unlike NMDA channels, Ca2+ permeable AMPA channels are not blocked by Mg2+, but are highly permeable to another potentially harmful endogenous cation, Zn2+. The targeting of these channels might provide efficacious new avenues in the therapy of certain neurological diseases.
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Even slower, sustained calcium influx through calcium-permeable AMPA receptors can be damaging through neuronal nitric oxide synthase activation, nitric oxide generation, and PARP-1 activation.
“Even slower, consistent Ca 2+ influx through Ca 2+ -permeable AMPA receptors can be damaging via activation of neuronal nitric oxide synthase and generation of nitric oxide and resultant activation of Poly(ADP-ribose) polymerase 1 (PARP-1), (Fig. 1b), [109, 110].”
From Parvalbumin interneuron vulnerability and brain disorders (2021) · cites this paper as [109]
If the pathological threshold is crossed, the electron transfer chain is disrupted, reactive oxygen species accumulate, the permeability transition pore opens, the outer mitochondrial membrane ruptures, cytochrome c is released, and an apoptotic program is activated.
“If the pathological threshold is crossed, the electron transfer chain is disrupted, reactive oxygen species accumulate, the permeability transition pore opens, the outer mitochondrial membrane ruptures, cytochrome c is released, and an apoptotic cell death program is activated [86,109].”
From Parvalbumin interneuron vulnerability and brain disorders (2021) · cites this paper as [109]
Zinc is more potent than calcium at disrupting mitochondrial function.
“Zinc is more potent than Ca 2+ in its ability to disrupt mitochondrial function [109].”
From Parvalbumin interneuron vulnerability and brain disorders (2021) · cites this paper as [109]
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References 50 · Cited by 256
- Authors
- Kwak, S., & Weiss, J. H.
- Affiliations
- The University of Tokyo (JP)
- University of California, Irvine (US)
- Corresponding author
- Weiss, John H
- Venue
- Current Opinion in Neurobiology
- Publisher
- Elsevier BV
- Published
- 2006-06
- Volume
- 16
- Issue
- 3
- Pages
- 281-287
- ISSN
- 0959-4388 (ISSN-L)
- OpenAlex
- W2059309243
- Cited by
- 256
- References
- 50
- Citations by year
- 2026: 5 · 2025: 8 · 2024: 2 · 2023: 5 · 2022: 7 · 2021: 13 · 2020: 10 · 2019: 9 · 2018: 15 · 2017: 9 · 2016: 6 · 2015: 20 · 2014: 10 · 2013: 14 · 2012: 24
- FWCI
- 2.07
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Current Opinion in Neurobiology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Muscular Dystrophy Association
- Ministry of Education, Culture, Sports, Science and Technology (14017020, 15016030, 16015228)
- National Institutes of Health (NS36548)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Keywords
- calcium-permeable AMPA receptors, excitotoxicity, neurodegeneration, stroke, amyotrophic lateral sclerosis, NMDA receptor overactivation, glutamate receptors, neuroprotection
- MeSH terms
- Amyotrophic Lateral Sclerosis, Animals, Calcium, Cell Membrane Permeability, Brain Ischemia, Humans, Zinc, Cell Death, Receptors, AMPA, Neurodegenerative Diseases, Calcium Signaling, Protein Subunits
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