Document Detail

Structural determinants of D-cycloserine efficacy at the NR1/NR2C NMDA receptors.
MedLine Citation:
PMID:  20164358     Owner:  NLM     Status:  MEDLINE    
We have studied relative efficacies of NR1 agonists glycine and d-cycloserine (DCS), and found efficacy to be dependent on the NR2 subunit. DCS shows partial agonism at NR1/NR2B but has higher relative efficacy than glycine at NR1/NR2C receptor. Molecular dynamics (MD) simulations of the NR1/NR2B and NR1/NR2C agonist binding domain dimer suggest only subtle differences in the interactions of DCS with NR1 binding site residues relative to glycine. The most pronounced differences were observed in the NR1/NR2C simulation between the orientation of helices F and G of the NR1 subunit. Interestingly, Helix F was previously proposed to influence receptor gating and to adopt an orientation depending on agonist efficacy. MD simulations and site-directed mutagenesis further suggest a role for residues at the agonist binding domain dimer interface in regulating DCS efficacy. To relate the structural rearrangements to receptor gating, we recorded single-channel currents from outside-out patches containing a single active NR1/NR2C receptor. DCS increased the mean open time and open probability of NR1/NR2C receptors compared with glycine. Maximum likelihood fitting of a gating model for NR1/NR2C receptor activation to the single-channel data suggests that DCS specifically accelerates the rate constant governing a fast gating step and reduces the closing rate. These changes appear to reflect a decreased activation energy for a pregating step and increased stability of the open states. We suggest that the higher efficacy of DCS at NR1/NR2C receptors involves structural rearrangements at the dimer interface and an effect on NR1/NR2C receptor pregating conformational changes.
Shashank M Dravid; Pieter B Burger; Anand Prakash; Matthew T Geballe; Roopali Yadav; Phuong Le; Kimberly Vellano; James P Snyder; Stephen F Traynelis
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  The Journal of neuroscience : the official journal of the Society for Neuroscience     Volume:  30     ISSN:  1529-2401     ISO Abbreviation:  J. Neurosci.     Publication Date:  2010 Feb 
Date Detail:
Created Date:  2010-02-18     Completed Date:  2010-03-19     Revised Date:  2014-09-22    
Medline Journal Info:
Nlm Unique ID:  8102140     Medline TA:  J Neurosci     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2741-54     Citation Subset:  IM    
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MeSH Terms
Antibiotics, Antitubercular / pharmacology*
Cell Line, Transformed
Computer Simulation
Cycloserine / pharmacology*
Dose-Response Relationship, Drug
Electric Stimulation / methods
Glycine / pharmacology
Ion Channel Gating / drug effects*,  genetics
Membrane Potentials / drug effects*,  genetics*
Microinjections / methods
Models, Molecular
Molecular Dynamics Simulation
Mutagenesis / genetics
Patch-Clamp Techniques / methods
Protein Interaction Domains and Motifs / drug effects,  genetics
Receptors, N-Methyl-D-Aspartate / genetics,  metabolism*
Xenopus laevis
Grant Support
Reg. No./Substance:
0/Antibiotics, Antitubercular; 0/NR1 NMDA receptor; 0/NR2C NMDA receptor; 0/Receptors, N-Methyl-D-Aspartate; 95IK5KI84Z/Cycloserine; TE7660XO1C/Glycine

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