Please use this identifier to cite or link to this item: https://doi.org/10.1124/mol.63.6.1212
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dc.titleMolecular determinants of proton-sensitive N-methyl-D-aspartate receptor gating
dc.contributor.authorLow, C.-M.
dc.contributor.authorLyuboslavsky, P.
dc.contributor.authorFrench, A.
dc.contributor.authorLe, P.
dc.contributor.authorWyatte, K.
dc.contributor.authorThiel, W.H.
dc.contributor.authorMarchan, E.M.
dc.contributor.authorIgarashi, K.
dc.contributor.authorKashiwagi, K.
dc.contributor.authorGernert, K.
dc.contributor.authorWilliams, K.
dc.contributor.authorTraynelis, S.F.
dc.contributor.authorZheng, F.
dc.date.accessioned2014-11-20T05:58:32Z
dc.date.available2014-11-20T05:58:32Z
dc.date.issued2003-06-01
dc.identifier.citationLow, C.-M., Lyuboslavsky, P., French, A., Le, P., Wyatte, K., Thiel, W.H., Marchan, E.M., Igarashi, K., Kashiwagi, K., Gernert, K., Williams, K., Traynelis, S.F., Zheng, F. (2003-06-01). Molecular determinants of proton-sensitive N-methyl-D-aspartate receptor gating. Molecular Pharmacology 63 (6) : 1212-1222. ScholarBank@NUS Repository. https://doi.org/10.1124/mol.63.6.1212
dc.identifier.issn0026895X
dc.identifier.urihttp://scholarbank.nus.edu.sg/handle/10635/108067
dc.description.abstractExtracellular protons inhibit N-methyl-D-aspartate (NMDA) receptors with an IC 50 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 IC 50 for protons (IC 50, 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.
dc.description.urihttp://libproxy1.nus.edu.sg/login?url=http://dx.doi.org/10.1124/mol.63.6.1212
dc.sourceScopus
dc.typeArticle
dc.contributor.departmentPHARMACOLOGY
dc.description.doi10.1124/mol.63.6.1212
dc.description.sourcetitleMolecular Pharmacology
dc.description.volume63
dc.description.issue6
dc.description.page1212-1222
dc.description.codenMOPMA
dc.identifier.isiut000183013900005
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