RGD Reference Report - Two adjacent phenylalanines in the NMDA receptor GluN2A subunit M3 domain interactively regulate alcohol sensitivity and ion channel gating. - Rat Genome Database

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Two adjacent phenylalanines in the NMDA receptor GluN2A subunit M3 domain interactively regulate alcohol sensitivity and ion channel gating.

Authors: Ren, Hong  Zhao, Yulin  Wu, Man  Dwyer, Donard S  Peoples, Robert W 
Citation: Ren H, etal., Neuropharmacology. 2017 Mar 1;114:20-33. doi: 10.1016/j.neuropharm.2016.11.013. Epub 2016 Nov 19.
RGD ID: 13432288
Pubmed: PMID:27876530   (View Abstract at PubMed)
PMCID: PMC5240780   (View Article at PubMed Central)
DOI: DOI:10.1016/j.neuropharm.2016.11.013   (Journal Full-text)

The N-methyl-d-aspartate (NMDA) receptor is a key target of ethanol action in the central nervous system. Alcohol inhibition of NMDA receptor function involves small clusters of residues in the third and fourth membrane-associated (M) domains. Previous results from this laboratory have shown that two adjacent positions in the M3 domain, F636 and F637, can powerfully regulate alcohol sensitivity and ion channel gating. In this study, we report that these positions interact with one another in the regulation of both NMDA receptor gating and alcohol action. Using dual mutant cycle analysis, we detected interactions among various substitution mutants at these positions with respect to regulation of glutamate EC50, steady-state to peak current ratios (Iss:Ip), mean open time, and ethanol IC50. This interaction apparently involves a balancing of forces on the M3 helix, such that the disruption of function due to a substitution at one position can be reversed by a similar substitution at the other position. For example, tryptophan substitution at F636 or F637 increased or decreased channel mean open time, respectively, but tryptophan substitution at both positions did not alter open time. Interestingly, the effects of a number of mutations on receptor kinetics and ethanol sensitivity appeared to depend upon subtle structural differences, such as those between the isomeric amino acids leucine and isoleucine, as they could not be explained on the basis of sidechain molecular volume or hydrophilicity.

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
response to ethanol involved_inIMP 13432288PMID:27876530ARUK-UCL 

Objects Annotated

Genes (Rattus norvegicus)
Grin2a  (glutamate ionotropic receptor NMDA type subunit 2A)


Additional Information