Reduced Ethanol Inhibition ofN-Methyl-d-aspartate Receptors by Deletion of the NR1 C0 Domain or Overexpression of α-Actinin-2 Proteins
The depressant actions of ethanol on central nervous system activity appear to be mediated by its actions on a number of important membrane associated ion channels including the N -methyl- d -aspartate (NMDA) subtype of ionotropic glutamate receptor. Although no specific site of action for ethanol o...
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Published in | The Journal of biological chemistry Vol. 275; no. 20; p. 15019 |
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Main Authors | , , , |
Format | Journal Article |
Language | English |
Published |
American Society for Biochemistry and Molecular Biology
19.05.2000
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Online Access | Get full text |
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Summary: | The depressant actions of ethanol on central nervous system activity appear to be mediated by its actions on a number of important
membrane associated ion channels including the N -methyl- d -aspartate (NMDA) subtype of ionotropic glutamate receptor. Although no specific site of action for ethanol on the NMDA receptor
has been found, previous studies suggest that the ethanol sensitivity of the receptor may be affected by intracellular C-terminal
domains of the receptor that regulate the calcium-dependent inactivation of the receptor. In the present study, co-expression
of the NR2A subunit and an NR1 subunit that lacks the alternatively spliced intracellular C1 cassette did not reduce the effects
of ethanol on channel function as measured by patch-clamp electrophysiology. Full inhibition was also observed in cells expressing
an NR1 subunit truncated at the end of the C0 domain (NR1 863stop ). However, the inhibitory effects of ethanol were reduced by expression of an NR1 C0 domain deletion mutant (NR1 Î839â863 ), truncation mutant (NR1 858stop ), or a triple-point mutant (Arg to Ala, Lys to Ala, and Asn to Ala at 859â861) previously shown to significantly reduce calcium-dependent
inactivation. A similar reduction in the effects of ethanol on wild-type NR1/2A but not NR1/2B or NR1/2C receptors was observed
after co-expression of full-length or truncated human skeletal muscle α-actinin-2 proteins that produce a functional knockout
of the C0 domain. The effects of ethanol on hippocampal and cortical NMDA-induced currents were similarly attenuated in low
calcium recording conditions, suggesting that a C0 domain-dependent process may confer additional ethanol sensitivity to NMDA
receptors. |
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ISSN: | 0021-9258 1083-351X |
DOI: | 10.1074/jbc.275.20.15019 |