Calcium-permeable AMPA channels in neurodegenerative disease and ischemia.
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.
Kwak
Shin
S
Department of Neurology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, 113-8655 Tokyo, Japan.
Weiss
John H
JH
D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D002545:Brain Ischemia / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002463:Cell Membrane Permeability / Q000502:physiology; D006801:Humans; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D018091:Receptors, AMPA / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D015032:Zinc / Q000378:metabolism / Q000633:toxicity
D021122:Protein Subunits; D018091:Receptors, AMPA; D015032:Zinc; D002118:Calcium