Effects of ethanol on NMDA receptors in brain: possibilities for Mg(2+)-ethanol interactions.
The major excitatory neurotransmitter in the CNS is L-glutamate, and one of the subtypes of L-glutamate receptors, the N-methyl-D-aspartate (NMDA) subtype, has been found to be quite sensitive to inhibition by low concentrations of ethanol (5-50 mM). The NMDA receptor-ion channels are unique in that they exhibit a voltage-dependent blockade by physiological concentrations of Mg2+, a blockade that is relieved as the cell membrane is depolarized. Several lines of evidence also suggest that the activity of this receptor-channel complex may be regulated through a high-affinity Mg2+ site, which is distinct from the channel-blocking site and could even be located on the extracellular domain of the protein. This high-affinity Mg2+ site has been shown to increase the binding of N-[1-(2-thienyl) cyclohexyl]piperidine within the ion channel, as well as the binding of competitive antagonist such as 3-(+/-)-carboxypiperazine-4-yl)-[1,2]-propyl-1-phosphonic acid and the receptor coactivator glycine. The relationship between the acute effects of ethanol on receptor activation and the regulatory properties of Mg2+ is not yet known, although the hypomagnesemia that occurs in chronic alcoholism could certainly have implications for receptor function. A significant amount of molecular characterization of the multiple isoforms of the NMDA receptor-ion channel will be required before the role of Mg2+ can be clarified and any relationship between Mg2+ regulation and ethanol inhibition established.
Michaelis
M L
ML
Department of Pharmacology and Toxicology, University of Kansas, Lawrence 66045.
Michaelis
E K
EK
D000437:Alcoholism / Q000150:complications / Q000503:physiopathology*; D000818:Animals; D001921:Brain / Q000503:physiopathology*; D006801:Humans; D007473:Ion Channels / Q000502:physiology*; D008274:Magnesium / Q000502:physiology*; D008275:Magnesium Deficiency / Q000503:physiopathology*; D008564:Membrane Potentials / Q000502:physiology; D017470:Receptors, Glutamate / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*
D007473:Ion Channels; D017470:Receptors, Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D008274:Magnesium