Allosteric potentiation by diazoxide of AMPA receptor currents and synaptic potentials.
Diazoxide (100-560 microM) reversibly increased the amplitude and duration of excitatory post-synaptic field potentials recorded in the dentate gyrus of hippocampal slices following stimulation of the perforant pathway. In rat cortex mRNA-injected Xenopus oocytes diazoxide (1-1000 microM) alone had little effect on membrane current, but rapidly and reversibly increased (up to 5-fold) current responses to (R,S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA, 30 microM), L-glutamate (100 microM), quisqualate (3 microM), kainate (100 microM) and domoate (3 microM), an effect that was neither mimicked by other activators of ATP-sensitive potassium channels nor blocked by glibenclamide. Diazoxide increased current amplitudes for all concentrations of the 'inactivating' ligands, AMPA, L-glutamate and quisqualate but had little effect on their EC50 values. In contrast, diazoxide increased the apparent potency of the 'non-inactivating' ligands, kainate and domoate, but increased the efficacy of saturating concentrations by only 10-20%. Diazoxide did not modify the competitive inhibition of AMPA and kainate currents by 6-nitro-7-sulfamoylbenzo[f]quinoxaline-2,3-dione (NBQX) and thus does not compete for the agonist site as do AMPA and kainate. Similarly, diazoxide neither inhibited the binding of [3H]AMPA or [3H]kainate to rat cortical membranes in competition experiments nor consistently modified the apparent [3H]AMPA affinity (Kd) or receptor density (Bmax) in saturation experiments. These data suggest that diazoxide acts at an allosteric site on the AMPA receptor/channel to potentiate activation in a manner dependent upon the properties of the excitatory agonist.
Randle
J C
JC
Institut de Recherches Servier, Suresnes, France.
Biton
C
C
Lepagnol
J M
JM
D000494:Allosteric Regulation; D000818:Animals; D003981:Diazoxide / Q000494:pharmacology*; D005998:Glycine / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects* / Q000502:physiology; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D016202:N-Methylaspartate / Q000494:pharmacology; D009865:Oocytes / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors*; D013569:Synapses / Q000187:drug effects* / Q000502:physiology; D014981:Xenopus; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D012333:RNA, Messenger; D018091:Receptors, AMPA; D005680:gamma-Aminobutyric Acid; D016202:N-Methylaspartate; D003981:Diazoxide; D005998:Glycine