Inhibition of energy metabolism by 3-nitropropionic acid activates ATP-sensitive potassium channels.
3-Nitropropionic acid (1 mM), which inhibits succinate dehydrogenase activity and reduces cellular energy, produces in the pyramidal cell layer of the hippocampal region CA1 a hyperpolarization for variable lengths of time before evoking an irreversible depolarization. Hyperpolarization is caused by an increased potassium conductance that is attenuated by glibenclamide (1-10 microM), a selective antagonist of ATP-sensitive potassium channels; in contrast, diazoxide (0.5 mM), an agonist at this channel, induces a hyperpolarization in CA1 neurons of rat hippocampal slices. The transient hyperpolarization after prolonged (ca. 1 h) application of 3-NPA is followed by a depolarization that is incompletely reversed by brief application of the glutamate antagonists (D-2-amino-5-phosphonopentanoic acid (APV), 6,7-dichloroquinoxaline-2,3-dione (CNQX), 3-(+/-)-2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP), 7-chloro-kynurenic acid (7Cl-KYN)). Early application of glibenclamide (within the initial 5 min) blocked or reduced hyperpolarization and accelerated the depolarization. These data suggest that metabolic inhibition by 3-NPA initially activates ATP-sensitive potassium channels. Events other than activation of glutamate receptors participate in the final depolarization resulting from uncoupling of oxidative phosphorylation.
Center for Research on Occupational and Environmental Toxicology, Oregon Health Science University, Portland 97201.
M
M
Riepe
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N
Hori
A C
AC
Ludolph
D O
DO
Carpenter
P S
PS
Spencer
C N
CN
Allen
D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000818:Animals; D004734:Energy Metabolism / Q000187:drug effects*; D018691:Excitatory Amino Acid Antagonists; D018698:Glutamic Acid; D006624:Hippocampus / Q000378:metabolism / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009574:Nitro Compounds; D015221:Potassium Channels / Q000187:drug effects* / Q000378:metabolism; D011422:Propionates / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains
D018691:Excitatory Amino Acid Antagonists; D009574:Nitro Compounds; D015221:Potassium Channels; D011422:Propionates; D018698:Glutamic Acid; D000255:Adenosine Triphosphate; C015392:3-nitropropionic acid