Neurotransmitter-gated membrane ion channels are among the most important target sites of alcohol action in the nervous system, although the manner in which alcohols modulate the function of these transmembrane proteins has not been established.
The aim of this project is to investigate the actions of alcohols and related compounds on neurotransmitter-gated ion channels thought to be involved in producing the intoxicating effects of alcohols in nervous tissue. Previous studies have shown that the function of the N-methyl-D-aspartate (NMDA) receptor-channel, a type of receptor for the excitatory neurotransmitter glutamate, is inhibited by intoxicating concentrations of ethanol. In addition, n-alcohols with 8 or fewer carbon atoms inhibit NMDA receptor-ion channel function, while larger n-alcohols do not. This """"""""cutoff effect"""""""" has been interpreted as an indication of a direct interaction of the alcohols with the receptor-ion channel protein. However, cutoff effects have also been proposed to be due to effects on membrane lipids, as cutoffs for the effect of alcohols on lipid membrane parameters have been reported. In addition, the effects of alcohols above the cutoff on these membrane lipid parameters are opposite to those of lower alcohols (i.e., alcohols above the cutoff decrease lipid mobility, whereas alcohols below the cutoff increase it). If alcohols produce their effects on NMDA receptor-channels by altering these membrane lipid parameters, then alcohols above the cutoff for receptor modulation should have an effect on receptor-channel function that is opposite to that of short-chain alcohols, and should also antagonize the effects of short-chain alcohols due to opposing effects on the membrane lipids. In mouse hippocampal neurons in primary culture, 1-dodecanol and 1-tetradecanol, both of which have been reported to decrease membrane lipid mobility, had no effect on NMDA-activated current, and did not alter ethanol inhibition of NMDA-activated current. These observations provide additional evidence for the hypothesis that alcohols affect NMDA receptor-ion channel function by interacting directly with the receptor protein.
| Yevenes, Gonzalo E; Peoples, Robert W; Tapia, Juan C et al. (2003) Modulation of glycine-activated ion channel function by G-protein betagamma subunits. Nat Neurosci 6:819-24 |
| Ren, Hong; Honse, Yumiko; Karp, Brian J et al. (2003) A site in the fourth membrane-associated domain of the N-methyl-D-aspartate receptor regulates desensitization and ion channel gating. J Biol Chem 278:276-83 |
| Kanemitsu, Yoshio; Hosoi, Masako; Zhu, Ping Jun et al. (2003) Dynorphin A inhibits NMDA receptors through a pH-dependent mechanism. Mol Cell Neurosci 24:525-37 |
| Peoples, Robert W; Ren, Hong (2002) Inhibition of N-methyl-D-aspartate receptors by straight-chain diols: implications for the mechanism of the alcohol cutoff effect. Mol Pharmacol 61:169-76 |
| Peoples, R W; Stewart, R R (2000) Alcohols inhibit N-methyl-D-aspartate receptors via a site exposed to the extracellular environment. Neuropharmacology 39:1681-91 |
