Allosteric potentiation by diazoxide of AMPA receptor currents and synaptic potentials

• Published in: European journal of pharmacology Vol. 247; no. 3; pp. 257 - 265
• Main Authors: Randle, John C.R., Biton, Catherine, Lepagnol, Jean M.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 15.11.1993; Elsevier
• Subjects: [ 3H]AMPA ( R, S)-α-Amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid) binding; [ 3H]Kainate binding; Allosteric Regulation; Animals; Antihypertensive agents; ATP-sensitive potassium channel activators; Biological and medical sciences; Cardiovascular system; Diazoxide - pharmacology; GABA receptor; gamma-Aminobutyric Acid - pharmacology; Glutamate receptors; Glycine - pharmacology; Hippocampal slices; Hippocampus - drug effects; Hippocampus - physiology; In Vitro Techniques; Kinetics; Male; Medical sciences; Membrane Potentials - drug effects; N-Methylaspartate - pharmacology; Oocytes - metabolism; Pharmacology. Drug treatments; Rats; Rats, Inbred F344; Rats, Wistar; Receptors, AMPA - antagonists & inhibitors; RNA, Messenger - metabolism; Synapses - drug effects; Synapses - physiology; Xenopus; Xenopus oocytes (rat cortex mRNA-injected); Glutamate receptors; [ 3H]Kainate binding; [ 3H]AMPA ( R, S)-α-Amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid) binding; Hippocampal slices; GABA receptor; ATP-sensitive potassium channel activators; Xenopus oocytes (rat cortex mRNA-injected); Rat; Central nervous system; Amphibia; Electrophysiology; Ionic channel; Glutamate receptor; Ionic current; Gabaergic receptor; Hypoglycemic agent; Messenger RNA; Mechanism of action; Xenopus laevis; Rodentia; Salientia; Glutamate; Vertebrata; AMPA receptor; Mammalia; Animal; Excitatory aminoacid; Antihypertensive agent; Field potential; ATP; Potassium; Hippocampus; Oocyte; Brain (vertebrata)
• ISSN: 0922-4106; 0014-2999
• DOI: 10.1016/0922-4106(93)90193-D

Diazoxide (100–560 μM) 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 μM) alone had little effect on membrane current, but rapidly and reversibly increased (up to 5-fold) current responses to ( R, S)-α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA, 30 μM), l-glutamate (100 μM), quisqualate (3 μM), kainate (100 μM) and domoate (3 μM), 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 EC 50 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 consistenty modified the apparent [ 3H]AMPA affinity ( K d) or receptor density ( B max) 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.