Ethanol inhibits alpha-amino-3-hydyroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor function in central nervous system neurons by stabilizing desensitization.
Ethanol actions on alpha-amino-3-hydyroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors were studied using voltage-clamp recordings from mouse cortical and hippocampal neurons. During whole-cell recordings ethanol (EtOH) inhibited AMPA receptor-mediated currents in a dose-dependent manner at concentrations from 10 to 500 mM. The steady-state component of AMPA-activated current was more sensitive to EtOH than the peak component. To examine the effect of EtOH on a well resolved peak current component, patches were excised from cultured cortical neurons, to which AMPA and EtOH were applied using a piezoelectric solution application system. Under this condition, the peak current was not inhibited significantly by EtOH. To further study possible mechanisms of EtOH inhibition, kainate and AMPA were used to evoke currents in the absence and presence of cyclothiazide. Ethanol inhibition was stronger when receptors were activated by low than high kainate concentrations. Cyclothiazide reduced inhibition by EtOH regardless of the agonist used to activate the receptor. Finally, EtOH inhibition was reduced in a point mutated (L497Y) GluRAi receptor that lacks desensitization. These findings suggest that EtOH inhibits AMPA receptors by stabilizing the desensitized state. Our results can explain some of the variation observed in EtOH inhibition in previous studies, and support the idea that physiologically relevant concentrations of EtOH can have a strong effect on AMPA receptor function.
Department of Molecular Physiology and Biophysics,Vanderbilt University School of Medicine, Nashville, Tenessee, USA.
Tommi
T
Möykkynen
Esa R
ER
Korpi
David M
DM
Lovinger
D019943:Amino Acid Substitution; D000818:Animals; D001581:Benzothiadiazines / Q000494:pharmacology; D002478:Cells, Cultured; D002490:Central Nervous System / Q000166:cytology; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D004347:Drug Interactions; D000431:Ethanol / Q000494:pharmacology*; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D006801:Humans; D007608:Kainic Acid / Q000494:pharmacology; D007930:Leucine / Q000235:genetics; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D017966:Pyramidal Cells / Q000187:drug effects / Q000502:physiology; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors*; D014443:Tyrosine / Q000235:genetics; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000037:antagonists & inhibitors
D001581:Benzothiadiazines; D002492:Central Nervous System Depressants; D018690:Excitatory Amino Acid Agonists; D018091:Receptors, AMPA; D000431:Ethanol; D014443:Tyrosine; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D007930:Leucine; C004639:cyclothiazide; D007608:Kainic Acid