Sites in the fourth membrane-associated domain regulate alcohol sensitivity of the NMDA receptor

Honse, Yumiko; Ren, Huajian; Lipsky, Robert H.; Peoples, Robert W.

doi:10.1016/j.neuropharm.2003.11.006

Cited by 46 publications

(79 citation statements)

References 29 publications

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“…In that study, we identified five positions in the GluN1 and GluN2A subunits that had not been previously shown to regulate ethanol sensitivity. Substitution mutations at a few of these individual positions, such as GluN2A(L824), had no effect on ethanol sensitivity by themselves (Honse et al, 2004) but influenced ethanol action only in concert with mutations at their paired position (Ren et al, 2012). In contrast, we found that tryptophan substitution at F636 in the M3 domain of GluN2A (Fig.…”

Section: Introductionmentioning

confidence: 62%

“…Reports from our laboratory and others have identified a small number of amino acid residues located in the M3 and M4 domains of NMDA receptor GluN1 and GluN2 subunits that influence ethanol sensitivity and channel function (Ronald et al, 2001;Ren et al, 2003bRen et al, , 2007Honse et al, 2004;Smothers and Woodward, 2006;Xu et al, 2012). The determinants of ethanol sensitivity and receptor function at each of these positions differ markedly from each other.…”

Section: Introductionmentioning

confidence: 92%

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A Novel Alcohol-Sensitive Position in the N-Methyl-d-Aspartate Receptor GluN2A Subunit M3 Domain Regulates Agonist Affinity and Ion Channel Gating

Ren

Zhao

et al. 2013

Mol Pharmacol

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Abundant evidence supports a role for N-methyl-D-aspartate (NMDA) receptor inhibition in the behavioral actions of ethanol, but the underlying molecular mechanisms have not been fully elucidated. We recently found that clusters of five positions in the third and fourth membrane-associated domains (M3 and M4) at the intersubunit interfaces form putative sites of alcohol action. In the present study, we found that one of these positions, NMDA receptor subunit, GluN2A(F636), can strongly regulate ethanol sensitivity, glutamate potency, and apparent desensitization: ethanol IC 50 values, peak (I p ) and steady-state (I ss ) glutamate EC 50 values, and steady-state to peak current ratio (I ss :I p ) values differed significantly among the mutants tested. Changes in glutamate affinity among the various mutants were not attributable to agonist trapping due to desensitization, as glutamate peak EC 50 values were correlated with values of both steady-state EC 50 and I ss :I p . The mean open times determined in selected mutants could be altered up to 4-fold but did not account for the changes in ethanol sensitivity. Ethanol sensitivity was significantly correlated with glutamate EC 50 and I ss :I p values, but the changes in ethanol IC 50 among mutants at this position do not appear to be secondary to changes in ion channel kinetics. Substitution of the isomeric amino acids leucine and isoleucine had markedly different effects on ethanol sensitivity, agonist potency, and desensitization, which is consistent with a stringent structural requirement for ion channel modulation by the side chain at this position. Our results indicate that GluN2A(F636) plays an important role in both channel function and ethanol inhibition in NMDA receptors.

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Section: Introductionmentioning

confidence: 62%

Section: Introductionmentioning

confidence: 92%

A Novel Alcohol-Sensitive Position in the N-Methyl-d-Aspartate Receptor GluN2A Subunit M3 Domain Regulates Agonist Affinity and Ion Channel Gating

Ren

Zhao

et al. 2013

Mol Pharmacol

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“…Data acquisition was conducted through the Clampex 9.2 program (Axon Instruments). Dose-response curves were generated from macroscopic peak currents (I) obtained from 7 different ACh concentrations (1,3,10,30,55,100, and 300 M ACh). Dose-response curves were fitted through the sigmoidal dose-response equation with variable slope using the GraphPad Prism 4 program (GraphPad),…”

Section: Methodsmentioning

confidence: 99%

Tryptophan-scanning Mutagenesis in the αM3 Transmembrane Domain of the Muscle-type Acetylcholine Receptor

Otero-Cruz

Baéz-Pagán

Caraballo-González

et al. 2007

Journal of Biological Chemistry

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“…Given the enhanced synaptic function of non-NMDAR in activity-dependent or cocaine-induced synaptic plasticity (Hayashi et al, 2000;Ungless et al, 2001), the rare inhibition of CeA non-NMDAR by alcohol may indicate a critical role of CeA non-NMDAR in alcohol reward and addiction. Alcohol inhibits NMDAR functions likely by allosteric modulation of the channel gating (Wright et al, 1996;Woodward, 2000;Honse et al, 2004;Smothers and Woodward, 2006). The molecular mechanisms involved in alcohol inhibition of postsynaptic non-NMDAR remain largely unknown at present.…”

Section: Acute Alcohol-induced Inhibition Of Glutamate Receptor Functmentioning

confidence: 99%

Involvement of Non-NMDA Glutamate Receptors in Central Amygdala in Synaptic Actions of Ethanol and Ethanol-Induced Reward Behavior

Zhu

Bie

Pan³

2007

J. Neurosci.

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Sites in the fourth membrane-associated domain regulate alcohol sensitivity of the NMDA receptor

Cited by 46 publications

References 29 publications

A Novel Alcohol-Sensitive Position in the N-Methyl-d-Aspartate Receptor GluN2A Subunit M3 Domain Regulates Agonist Affinity and Ion Channel Gating

A Novel Alcohol-Sensitive Position in the N-Methyl-d-Aspartate Receptor GluN2A Subunit M3 Domain Regulates Agonist Affinity and Ion Channel Gating

Tryptophan-scanning Mutagenesis in the αM3 Transmembrane Domain of the Muscle-type Acetylcholine Receptor

Involvement of Non-NMDA Glutamate Receptors in Central Amygdala in Synaptic Actions of Ethanol and Ethanol-Induced Reward Behavior

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