Premium
Enhanced Ethanol Inhibition of Recombinant N ‐methyl‐ D ‐aspartate Receptors by Magnesium: Role of NR3A Subunits
Author(s) -
Jin Chun,
Thetford Smothers C.,
Woodward John J.
Publication year - 2008
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.1530-0277.2008.00667.x
Subject(s) - nmda receptor , glutamate receptor , chemistry , ethanol , receptor , glycine receptor , patch clamp , biophysics , biochemistry , inhibitory postsynaptic potential , pharmacology , neurotransmitter receptor , gabaa receptor , microbiology and biotechnology , glycine , biology , endocrinology , amino acid
Background: The effects of ethanol on brain function are thought to be partly because of altered activity of ion channels that regulate synaptic activity. Results from previous studies from this lab and others have shown that ethanol inhibits the function of the N ‐methyl‐ d ‐aspartate (NMDA) receptors, a calcium‐permeable ion channel activated by the neurotransmitter glutamate. Factors that influence the acute sensitivity of NMDA receptors to ethanol may be critical in determining how neurons and neuronal networks respond to the presence of ethanol. In this study, we have examined the effect of physiologically relevant concentrations of magnesium on the ethanol sensitivity of recombinant NMDA receptors and how ethanol inhibition under these conditions is influenced by the NR3A subunit. Methods: Recombinant cDNAs encoding NMDA receptor subunits were expressed in human embryonic kidney 293 cells. Whole‐cell patch‐clamp electrophysiology was used to measure currents induced by rapid application of glutamate in the absence and presence of ethanol. Results: In magnesium‐free recording solution, ethanol inhibited glutamate‐mediated currents in cells transfected with NMDA receptor subunits. The magnitude of ethanol inhibition was significantly enhanced when recordings were carried out in media containing 1 mM magnesium. This effect was reversible and required magnesium‐sensitive receptors. Magnesium did not enhance ethanol inhibition of glycine‐activated NR1/NR3A/NR3B receptors. However, NR3A co‐expression prevented the enhancement of ethanol’s inhibitory effect on receptors composed of NR2A but not NR2B subunits. Conclusions: These results suggest that under physiological conditions, NR3A may be an important regulator of the acute ethanol sensitivity of brain NMDA receptors.