| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
J Biol Chem, Vol. 275, Issue 20, 15019-15024, May 19, 2000
From the Department of Pharmacology and Toxicology, Medical College
of Virginia Campus, Virginia Commonwealth University,
Richmond, Virginia 23298
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
(NR1863stop). However, the inhibitory effects of
ethanol were reduced by expression of an NR1 C0 domain deletion mutant
(NR1
Reduced Ethanol Inhibition of
N-Methyl-D-aspartate Receptors by Deletion of
the NR1 C0 Domain or Overexpression of
-Actinin-2 Proteins*
839-863), truncation mutant
(NR1858stop), or a triple-point mutant (Arg to Ala, Lys to
Ala, and Asn to Ala at 859-861) 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 
-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.
*
This work was supported by AA09986 and AA00238 (to
J. J. W.) and by DA07027 (to D. L. A.).The costs of publication of this article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Dept. of Pharmacology
and Toxicology, P. O. Box 980524, MCV Station, Virginia Commonwealth
University, Richmond, VA 23298. Tel.: 804-828-8902; Fax: 804-828-1532;
E-mail: jwoodwar@hsc.vcu.edu.
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
 |
|
  N. Suvarna, S. L. Borgland, J. Wang, K. Phamluong, Y. P. Auberson, A. Bonci, and D. Ron Ethanol Alters Trafficking and Functional N-Methyl-D-aspartate Receptor NR2 Subunit Ratio via H-Ras J. Biol. Chem., September 9, 2005; 280(36): 31450 - 31459. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. C. Nelson, A. C. Heath, K. K. Bucholz, P. A. F. Madden, Q. Fu, V. Knopik, M. T. Lynskey, M. T. Lynskey, J. B. Whitfield, D. J. Statham, et al. Genetic Epidemiology of Alcohol-Induced Blackouts Arch Gen Psychiatry, March 1, 2004; 61(3): 257 - 263. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. M. Ronald, T. Mirshahi, and J. J. Woodward Ethanol Inhibition of N-Methyl-D-aspartate Receptors Is Reduced by Site-directed Mutagenesis of a Transmembrane Domain Phenylalanine Residue J. Biol. Chem., November 21, 2001; 276(48): 44729 - 44735. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| All ASBMB Journals | Molecular and Cellular Proteomics |
| Journal of Lipid Research | ASBMB Today |
