Molecular Determinants of Proton-Sensitive  <i>N</i>-Methyl-d-aspartate Receptor Gating

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

doi:10.1124/mol.63.6.1212

Cited by 93 publications

(143 citation statements)

References 46 publications

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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: 78%

“…Extensive mutagenesis throughout most of the extracellular regions of the NR1 protein such as the agonist binding domain and the N-terminal domain is without effect on pH-sensitive gating (Low et al, 2003). This result is consistent with the lack of effect of pH on experimentally determined coagonist dose-response relationships (Tang et al, 1990;CullCandy, 1990,1991), the current relaxation time course after agonist removal (Fig.…”

Section: Structural Implicationssupporting

confidence: 77%

“…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).…”

Section: Structural Implicationsmentioning

confidence: 99%

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Protons Trap NR1/NR2B NMDA Receptors in a Nonconducting State

Banke¹,

Dravid²,

Traynelis³

2005

J. Neurosci.

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NMDA receptors are highly expressed in the CNS and are involved in excitatory synaptic transmission, as well as synaptic plasticity. Given that overstimulation of NMDA receptors can cause cell death, it is not surprising that these channels are under tight control by a series of inhibitory extracellular ions, including zinc, magnesium, and H ϩ . We studied the inhibition by extracellular protons of recombinant NMDA receptor NR1/NR2B single-channel and macroscopic responses in transiently transfected human embryonic kidney HEK 293 cells using patch-clamp techniques. We report that proton inhibition proceeds identically in the absence or presence of agonist, which rules out the possibility that protonation inhibits receptors by altering coagonist binding. The response of macroscopic currents in excised patches to rapid jumps in pH was used to estimate the microscopic association and dissociation rates for protons, which were 1.4 ϫ 10 9 M Ϫ1 sec Ϫ1 and 110 -196 sec Ϫ1 , respectively (K d corresponds to pH 7.2). Protons reduce the open probability without altering the time course of desensitization or deactivation. Protons appear to slow at least one time constant describing the intra-activation shut-time histogram and modestly reduce channel open time, which we interpret to reflect a reduction in the overall channel activation rate and possible proton-induced termination of openings. This is consistent with a modest proton-dependent slowing of the macroscopic response rise time. From these data, we propose a physical model of proton inhibition that can describe macroscopic and single-channel properties of NMDA receptor function over a range of pH values.

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Section: Figure 6 Protonation Of Nr1/nr2b Channels Alters the Shut-tsupporting

confidence: 78%

Section: Structural Implicationssupporting

confidence: 77%

Section: Structural Implicationsmentioning

confidence: 99%

See 1 more Smart Citation

Protons Trap NR1/NR2B NMDA Receptors in a Nonconducting State

Banke¹,

Dravid²,

Traynelis³

2005

J. Neurosci.

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“…These residues are part of a region that corresponds to the Lurcher mouse phenotype that is characterized by a constitutively open NMDAR channel (Kohda et al, 2000;Kashiwagi et al, 2002). Recent work has revealed that the proton sensitivity of the NMDAR is reduced by the disruptive mutation of T648 (Low et al, 2003). It has been proposed that T648 is part of a conformational change involving movement of the M3 segment during ligand gating of the NMDAR (Low et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Differential binding properties of [3H]dextrorphan and [3H]MK-801 in heterologously expressed NMDA receptors

et al. 2005

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The N-methyl-D-aspartate receptor (NMDAR) antagonists: MK-801, phencyclidine and ketamine are open-channel blockers with limited clinical value due to psychotomimetic effects. Similarly, the psychotomimetic effects of the dextrorotatory opioids, dextromethorphan and its metabolite dextrorphan, derive from their NMDAR antagonist actions. Differences in the use dependency of blockade, however, suggest that the binding sites for MK-801 and dextrorphan are distinct. In the absence of exogenous glutamate and glycine, the rate of association of

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“…The NMDA receptor (NR1 -NR2a) is open for only approximately one third of the time when glutamate is bound (in the absence of magnesium) [44,51] which, on the face of it, means that glutamate itself is a partial agonist. However, it is likely that the relatively low maximum P open could result from block by H þ , and perhaps by contaminant Zn 2þ [52,53]. It seems that the NMDA receptor resembles others in that the singlechannel conductance is independent of the nature of the agonist that acts at the glutamate sites [54,55].…”

Section: Trends Inmentioning

confidence: 99%

Function and structure in glycine receptors and some of their relatives

Colquhoun

Sivilotti

2004

Trends in Neurosciences

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In the field of ligand-gated ion channels, recent developments, both in the knowledge of structure and in the measurement of function at the single-channel level, have allowed a sensible start to be made on understanding the relationship between structure and function in these proteins. In this review, the cases of glycine, nicotinic ACh and glutamate receptors are compared and contrasted, and problems such as how binding of agonist causes the channel to open, and why partial agonists are partial, are considered. Some observations, both structural and functional, suggest that more attention needs to be paid to conformational changes that occur before the channel opens. Such changes might account for the interaction found between subunits of the glycine receptor while it is still shut and, perhaps, the agonist-dependent structural changes seen in AMPA receptors. They might also complicate our understanding of the binding-gating problem.'Francis Crick…said that in the pioneering days of structure determination researchers were driven by the conviction that once they had solved a biological structure, its function or mechanism would become immediately obvious. It came as a shock when they found this was not necessarily so and that the opposite was more frequently true.' [1] This review is a biased discussion of some recent work on glycine receptors, with reference to some other receptors where it seems appropriate, and where length allows. The aim is to discuss what can be learned about reaction mechanisms from single-channel analysis, and the extent to which it can be related to structure [2][3][4]. Desensitization is not considered owing to lack of space. As will be seen, it appears that, despite big advances in both areas, the link between them is still weak.What is known about structure? Nicotinic ACh receptors Nicotinic ACh receptors have five subunits (two a and three non-a) arranged quasi-symmetrically around the channel. Our knowledge of structure comes mainly from the electron microscopy work by Unwin and co-workers on Torpedo receptors [5,6], and from the crystal structure of the Lymnea stagnalis ACh-binding protein [7,8]. The latter is a soluble pentamer of five identical subunits, each with 210 amino acids (less than half the 437 residues of the human a1 subunit), and with 20 -24% sequence identity with the extracellular domain of nicotinic subunits. Unwin's work (resolution up to 4 Å ) is still the only source of structural knowledge about the four receptor transmembrane domains (M1 to M4) which form the channel, or about heteromeric receptors (Figure 1). Glycine receptorsGlycine receptors are pentamers formed either from a subunits alone, or from both a and b subunits. Heteromeric glycine receptors have subunit composition a 3 b 2 [9-11] and three agonist-binding sites, rather than the two sites found in nicotinic ACh or GABA A receptors. The homomeric glycine receptor is discussed later. There is no direct evidence about the structure of glycine receptors, so structural inferences are based solely on...

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Molecular Determinants of Proton-Sensitive N-Methyl-d-aspartate Receptor Gating

Cited by 93 publications

References 46 publications

Protons Trap NR1/NR2B NMDA Receptors in a Nonconducting State

Protons Trap NR1/NR2B NMDA Receptors in a Nonconducting State

Differential binding properties of [3H]dextrorphan and [3H]MK-801 in heterologously expressed NMDA receptors

Function and structure in glycine receptors and some of their relatives

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