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Effects of Ethanol on NMDA Receptors in Brain: Possibilities for Mg 2+ ‐Ethanol Interactions
Author(s) -
Michaelis Mary L.,
Michaelis Elias K.
Publication year - 1994
Publication title -
alcoholism: clinical and experimental research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 153
eISSN - 1530-0277
pISSN - 0145-6008
DOI - 10.1111/j.1530-0277.1994.tb00083.x
Subject(s) - ethanol , nmda receptor , receptor , chemistry , neuroscience , pharmacology , biochemistry , psychology , medicine
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 Mg 2+ , 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 Mg 2+ site, which is distinct from the channel‐blocking site and could even be located on the extracellular domain of the protein. This high‐affinity Mg 2+ 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 Mg 2+ 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 Mg 2+ can be clarified and any relationship between Mg 2+ regulation and ethanol inhibition established.