QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.103.050666v1 306/2/546    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Möykkynen, T. Articles by Lovinger, D. M. Search for Related Content PubMed PubMed Citation Articles by Möykkynen, T. Articles by Lovinger, D. M.

NEUROPHARMACOLOGY

Ethanol Inhibits -Amino-3-hydyroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptor Function in Central Nervous System Neurons by Stabilizing Desensitization

Department of Molecular Physiology and Biophysics (T.M., D.M.L.), Vanderbilt University School of Medicine, Nashville, Tennessee; Department of Pharmacology and Clinical Pharmacology (T.M., E.R.K.), University of Turku, Turku, Finland; Institute of Biomedicine (E.R.K.), Pharmacology, University of Helsinki, Helsinki, Finland; and Laboratory for Integrative Neuroscience (D.M.L.), National Institute on Alcohol Abuse and Alcoholism, Rockville, Maryland

Ethanol actions on -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.

Address correspondence to: Dr. David M. Lovinger, Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, 12420 Parklawn Dr., Rockville, MD 20852. E-mail: lovindav{at}mail.nih.gov

This article has been cited by other articles:

				A. M. Dopico and D. M. Lovinger Acute Alcohol Action and Desensitization of Ligand-Gated Ion Channels Pharmacol. Rev., March 1, 2009; 61(1): 98 - 114. [Abstract] [Full Text] [PDF]

				S. K. Coleman, T. Moykkynen, A. Jouppila, S. Koskelainen, C. Rivera, E. R Korpi, and K. Keinanen Agonist Occupancy Is Essential for Forward Trafficking of AMPA Receptors J. Neurosci., January 14, 2009; 29(2): 303 - 312. [Abstract] [Full Text] [PDF]

				J. Liu, T. Vaithianathan, K. Manivannan, A. Parrill, and A. M. Dopico Ethanol Modulates BKCa Channels by Acting as an Adjuvant of Calcium Mol. Pharmacol., September 1, 2008; 74(3): 628 - 640. [Abstract] [Full Text] [PDF]

				H. Ren, A. K. Salous, J. M. Paul, K. A. Lamb, D. S. Dwyer, and R. W. Peoples Functional Interactions of Alcohol-sensitive Sites in the N-Methyl-D-aspartate Receptor M3 and M4 Domains J. Biol. Chem., March 28, 2008; 283(13): 8250 - 8257. [Abstract] [Full Text] [PDF]

				W. Zhu, B. Bie, and Z. Z. Pan Involvement of Non-NMDA Glutamate Receptors in Central Amygdala in Synaptic Actions of Ethanol and Ethanol-Induced Reward Behavior J. Neurosci., January 10, 2007; 27(2): 289 - 298. [Abstract] [Full Text] [PDF]

				S. K. Coleman, T. Moykkynen, C. Cai, L. von Ossowski, E. Kuismanen, E. R. Korpi, and K. Keinanen Isoform-Specific Early Trafficking of AMPA Receptor Flip and Flop Variants J. Neurosci., October 25, 2006; 26(43): 11220 - 11229. [Abstract] [Full Text] [PDF]

				M. Carta, M. Mameli, and C. F. Valenzuela Alcohol Potently Modulates Climbing Fiber->Purkinje Neuron Synapses: Role of Metabotropic Glutamate Receptors J. Neurosci., February 15, 2006; 26(7): 1906 - 1912. [Abstract] [Full Text] [PDF]

				M. Mameli, P. A. Zamudio, M. Carta, and C. F. Valenzuela Developmentally Regulated Actions of Alcohol on Hippocampal Glutamatergic Transmission J. Neurosci., August 31, 2005; 25(35): 8027 - 8036. [Abstract] [Full Text] [PDF]