ALLOSTERIC POTENTIATION BY DIAZOXIDE OF AMPA RECEPTOR CURRENTS AND SYNAPTIC POTENTIALS

Diazoxide (100-560 muM) 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 muM) 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 muM), L-glutamate (100 muM), quisqualate (3 muM), kainate (100 muM) and domoate (3 muM), 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 [H-3]AMPA or [H-3]kainate to rat cortical membranes in competition experiments nor consistently modified the apparent [H-3]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.