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.
Riepe
M
M
Center for Research on Occupational and Environmental Toxicology, Oregon Health Science University, Portland 97201.
Hori
N
N
Ludolph
A C
AC
Carpenter
D O
DO
Spencer
P S
PS
Allen
C N
CN
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