Functional interactions of alcohol-sensitive sites in the N-methyl-D-aspartate receptor M3 and M4 domains.

The Journal of Biological Chemistry
H RenR W Peoples

Abstract

The N-methyl-D-aspartate receptor is an important mediator of the behavioral effects of ethanol in the central nervous system. Previous studies have demonstrated sites in the third and fourth membrane-associated (M) domains of the N-methyl-D-aspartate receptor NR2A subunit that influence alcohol sensitivity and ion channel gating. We investigated whether two of these sites, Phe-637 in M3 and Met-823 in M4, interactively regulate the ethanol sensitivity of the receptor by testing dual substitution mutants at these positions. A majority of the mutations decreased steady-state glutamate EC(50) values and maximal steady-state to peak current ratios (I(ss)/I(p)), whereas only two mutations altered peak glutamate EC(50) values. Steady-state glutamate EC(50) values were correlated with maximal glutamate I(ss)/I(p) values, suggesting that changes in glutamate potency were attributable to changes in desensitization. In addition, there was a significant interaction between the substituents at positions 637 and 823 with respect to glutamate potency and desensitization. IC(50) values for ethanol among the mutants varied over the approximate range 100-325 mm. The sites in M3 and M4 significantly interacted in regulating ethanol sensitivity,...Continue Reading

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Citations

Apr 6, 2011·Proceedings of the National Academy of Sciences of the United States of America·Tianna R HicklinMichael D Browning
Nov 2, 2011·The Journal of Pharmacology and Experimental Therapeutics·Patricio A CastroLuis G Aguayo
Mar 10, 2009·Pharmacological Reviews·Alex M Dopico, David M Lovinger
Dec 11, 2013·Biochemistry Research International·Sergey Vladimirovich LelevichEugene Victorovich Barkovsky
Jun 9, 2015·Neuropharmacology·Yulin ZhaoRobert W Peoples
Aug 7, 2013·Alcoholism, Clinical and Experimental Research·Jennifer L HelferBrian R Christie
Jun 4, 2016·Cellular and Molecular Neurobiology·Yongjun SunZibin Gao
Jan 8, 2018·Neurochemical Research·Mickaël Naassila, Olivier Pierrefiche
Dec 25, 2019·Alcoholism, Clinical and Experimental Research·Paula A ZamudioJohn J Woodward
Dec 18, 2019·Médecine sciences : M/S·Camille SautreuilBruno J Gonzalez
Jun 11, 2011·Critical Reviews in Clinical Laboratory Sciences·Silvia Alfonso-Loeches, Consuelo Guerri

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