2002
DOI: 10.1016/s0896-6273(01)00560-8
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Molecular Rearrangements of the Extracellular Vestibule in NMDAR Channels during Gating

Abstract: Many N-methyl-D-aspartate receptor (NMDAR) channel blockers that have therapeutic potential can be trapped in the closed state. Using a combination of the substituted cysteine accessibility method and open channel blockers, we found that the M3 segment forms the core of the extracellular vestibule, including a deep site for trapping blockers. The M3 segment, as well as more superficial parts of the extracellular vestibule, undergo extensive remodeling during channel closure, but do not define the activation ga… Show more

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Cited by 102 publications
(168 citation statements)
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“…Similar arguments have been proposed for selective proton effects on a single unidirectional rate constant for mechanosensitive channels (Guharay and Sachs, 1985). This proposed effect of protons on the opening rate is consistent with previous suggestions that protons act in the linker region (Low et al, 2003) proposed to couple the effects of agonist binding to the S1S2 domain to the transmembrane pore-forming elements that perform gating (Jones et al, 2002;Sobolevsky et al, 2002). Figure 7 illustrates a set of physical models of NMDA receptor gating in which the receptor can bind a proton anywhere along the reaction pathway, except during pregating steps required for activation.…”
Section: Figure 6 Protonation Of Nr1/nr2b Channels Alters the Shut-tsupporting
confidence: 90%
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“…Similar arguments have been proposed for selective proton effects on a single unidirectional rate constant for mechanosensitive channels (Guharay and Sachs, 1985). This proposed effect of protons on the opening rate is consistent with previous suggestions that protons act in the linker region (Low et al, 2003) proposed to couple the effects of agonist binding to the S1S2 domain to the transmembrane pore-forming elements that perform gating (Jones et al, 2002;Sobolevsky et al, 2002). Figure 7 illustrates a set of physical models of NMDA receptor gating in which the receptor can bind a proton anywhere along the reaction pathway, except during pregating steps required for activation.…”
Section: Figure 6 Protonation Of Nr1/nr2b Channels Alters the Shut-tsupporting
confidence: 90%
“…Mutagenesis work together with homology modeling of the extracellular domains of the NR1 subunit suggest that residues at which substitutions strongly influence proton-sensitive gating cluster in two regions, both of which reside close to the linker connecting the agonist binding domain to transmembrane pore-forming elements (Low et al, 2003). This region is ideally localized to influence the coupling of agonist binding to channel activation (Kohda et al, 2000;Jones et al, 2002;Sobolevsky et al, 2002). However, it remains unclear whether the structural elements formed by this linker region comprise or contribute to the proton sensor or whether this result instead reflects reciprocal interactions between the gating machinery and a distant and as yet unidentified proton sensor.…”
Section: Structural Implicationsmentioning
confidence: 99%
“…A vector for enhanced green fluorescent protein (pEGFP-C1; Clontech, Palo Alto, CA) was cotransfected at a ratio of 1:9 (pEGFP-C1:GluR subunit). Oocytes were prepared, injected, and maintained as described Sobolevsky et al, 2002). Recordings were made 1-6 d after transfections or injections.…”
Section: Molecular Biology and Heterologous Expressionmentioning
confidence: 99%
“…Cysteine-substituted GluR channels were probed from the extracellular side of the membrane with the positively charged MTSET. MTSET-containing solutions were prepared, stored, and applied as described previously (Sobolevsky et al, 2002). Accessibility of substituted cysteines was determined using steadystate reaction protocols (Sobolevsky et al, 2002).…”
Section: Experimental Protocolsmentioning
confidence: 99%
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