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National Neuroscience Institute and Department of Pharmacology, National University of Singapore, Singapore (C.-M.L.); Department of Pharmacology, Emory University School of Medicine, Rollins Research Center, Atlanta, Georgia (P.L., A.F., P.L., K.Wy., W.H.T., E.M.M., S.F.T., F.Z.); Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan (K.I., K.K.); BimCore Computing Center, Emory University, Atlanta, Georgia (K.G.); Department of Physiology and Pharmacology, State University of New York Health Science Center, Brooklyn, New York (K.Wi.); and Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas (F.Z.)
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 µM 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.
Address correspondence to: Dr. Fang Zheng, Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, 4301 W. Markham St., Little Rock, AR 77203-7199. E-mail: zhengfang{at}nams.edu
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