Molecular determinants of proton-sensitive N-methyl-D-aspartate receptor gating

Chian-Ming Low; Polina Lyuboslavsky; Adam French; Phuong Le; Karen Wyatte; William H Thiel; Edward M Marchan; Kazuei Igarashi; Keiko Kashiwagi; Kim Gernert; Keith Williams; Stephen F Traynelis; Fang Zheng

doi:10.1124/mol.63.6.1212

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Molecular determinants of proton-sensitive N-methyl-D-aspartate receptor gating

Journal article

Peer reviewed

Molecular determinants of proton-sensitive N-methyl-D-aspartate receptor gating

Chian-Ming Low, Polina Lyuboslavsky, Adam French, Phuong Le, Karen Wyatte, William H Thiel, Edward M Marchan, Kazuei Igarashi, Keiko Kashiwagi, Kim Gernert, …

Molecular pharmacology, Vol.63(6), pp.1212-1222

06/2003

DOI: 10.1124/mol.63.6.1212

PMID: 12761330

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Abstract

Extracellular protons inhibit N-methyl-D-aspartate (NMDA) receptors with an IC50 value in the physiological pH range. To identify the molecular determinants of proton sensitivity, we used scanning mutagenesis of the NR1 subunit to search for residues that control proton inhibition of NMDA receptors. Homology modeling of the extracellular domains suggested that residues at which mutations perturbed pH sensitivity were localized in discrete regions. The majority of mutations that strongly affected proton sensitivity were clustered in the extracellular end of the second transmembrane domain (M3) and adjacent linker leading to the S2 portion of the glycine-binding domain of NR1. Mutations in NR2A confirmed that the analogous region controls the pH sensitivity of this subunit and also identified the linker region between the third transmembrane domain (M4) and the S2 portion of the NR2 glutamate binding domain as an additional determinant of proton sensitivity. One mutant receptor, NR1(A649C)/NR2A(A651T), showed a 145-fold reduction in the IC50 for protons (IC50, 17.3 microM corresponding to pH 4.9). The M3-S2 linker region has been suggested to control NMDA receptor gating, leading to the hypothesis that the proton sensor and receptor gate may be structurally and functionally integrated.

Mutation

Protons

Amino Acid Sequence

N-Methylaspartate - metabolism

Oocytes - metabolism

Xenopus laevis

Receptors, N-Methyl-D-Aspartate - metabolism

Models, Molecular

Molecular Sequence Data

Protein Subunits - metabolism

Receptors, N-Methyl-D-Aspartate - genetics

Sequence Homology, Amino Acid

Animals

Hydrogen-Ion Concentration

Protein Subunits - genetics

Details

Title: Subtitle: Molecular determinants of proton-sensitive N-methyl-D-aspartate receptor gating
Creators: Chian-Ming Low - Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, 4301 W. Markham St., Little Rock, AR 77203-7199, USA
Polina Lyuboslavsky
Adam French
Phuong Le
Karen Wyatte
William H Thiel
Edward M Marchan
Kazuei Igarashi
Keiko Kashiwagi
Kim Gernert
Keith Williams
Stephen F Traynelis
Fang Zheng
Resource Type: Journal article
Publication Details: Molecular pharmacology, Vol.63(6), pp.1212-1222
DOI: 10.1124/mol.63.6.1212
PMID: 12761330
ISSN: 0026-895X
eISSN: 1521-0111
Grant note: NS 21975 / NINDS NIH HHS NS 35047 / NINDS NIH HHS NS 36654 / NINDS NIH HHS
Language: English
Date published: 06/2003
Academic Unit: Cardiovascular Medicine; Internal Medicine
Record Identifier: 9984094555602771

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