Ethanol inhibition of recombinant heteromeric NMDA channels in the presence and absence of modulators
Biochemistry & Molecular Pharmacology
Graduate School of Biomedical Sciences; Department of Pharmacology; Program in Neuroscience
Medical Subject Headings
Animals; Electrophysiology; Ethanol; Female; Ion Channels; Kynurenic Acid; Magnesium; N-Methylaspartate; Oxidation-Reduction; Receptors, N-Methyl-D-Aspartate; Recombinant Proteins; Xenopus laevis; Zinc
Life Sciences | Medicine and Health Sciences
The NMDA receptor/channel has been shown to be inhibited by ethanol in the clinically relevant range 25-100 mM. We studied heteromeric assemblies (NR1b/NR2) of the NMDA receptor, expressed in oocytes, to address three questions regarding this inhibition, and discovered the following: (1) The inhibition was nearly equivalent when ethanol was coapplied with the agonist, and when ethanol was introduced after steady-state current was established, suggesting that ethanol does not act by interfering with the activation process of the NMDA receptor. (2) The degree of inhibition was controlled by the NR2 subunit, with both NR2A and NR2B significantly more sensitive to ethanol than NR2C and NR2D. (3) Manipulation of the NMDA receptor with a number of agents that normally modulate it did not alter the degree of inhibition produced by ethanol. The presence of Mg2+ (3 and 12.5 microM), Zn2+ (1 and 10 microM), or the glycine antagonist 7-chlorokynurenic acid (1.25 or 5 microM), did not alter the ethanol sensitivity of heteromeric (NR1b/NR2A, NR1b/NR2B, NR1b/NR2C) NMDA receptors. Redox modulation of the NMDA receptor by dithiothreitol (2 mM) or 5,5'-dithiobis(2-nitrobenzoic acid) (1 mM) also did not alter the degree to which ethanol inhibits NMDA receptors. Taken together, these results indicate that the ethanol sensitivity of native NMDA receptors, which likely exist in heteromeric form, results from actions at a site different from those of known modulators of the receptor.
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Citation: J Neurochem. 1995 Jul;65(1):140-8.
Journal of neurochemistry
Chu, Benson; Anantharam, Vellareddy; and Treistman, Steven N., "Ethanol inhibition of recombinant heteromeric NMDA channels in the presence and absence of modulators" (1995). GSBS Student Publications. 222.