Structural determinants of D-cycloserine efficacy at the NR1/NR2C NMDA receptors

Shashank M. Dravid, Pieter B. Burger, Anand Prakash, Matthew T. Geballe, Roopali Yadav, Phuong Le, Kimberly Vellano, James P. Snyder, Stephen F. Traynelis

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Pages (from-to)2741-2754
Number of pages14
JournalJournal of Neuroscience
Volume30
Issue number7
DOIs
StatePublished - Feb 17 2010

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Cycloserine
Glycine
Molecular Dynamics Simulation
Site-Directed Mutagenesis
NR2C NMDA receptor
NR1 NMDA receptor
Binding Sites

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)

Cite this

Dravid, S. M., Burger, P. B., Prakash, A., Geballe, M. T., Yadav, R., Le, P., ... Traynelis, S. F. (2010). Structural determinants of D-cycloserine efficacy at the NR1/NR2C NMDA receptors. Journal of Neuroscience, 30(7), 2741-2754. https://doi.org/10.1523/JNEUROSCI.5390-09.2010

Structural determinants of D-cycloserine efficacy at the NR1/NR2C NMDA receptors. / Dravid, Shashank M.; Burger, Pieter B.; Prakash, Anand; Geballe, Matthew T.; Yadav, Roopali; Le, Phuong; Vellano, Kimberly; Snyder, James P.; Traynelis, Stephen F.

In: Journal of Neuroscience, Vol. 30, No. 7, 17.02.2010, p. 2741-2754.

Research output: Contribution to journalArticle

Dravid, SM, Burger, PB, Prakash, A, Geballe, MT, Yadav, R, Le, P, Vellano, K, Snyder, JP & Traynelis, SF 2010, 'Structural determinants of D-cycloserine efficacy at the NR1/NR2C NMDA receptors', Journal of Neuroscience, vol. 30, no. 7, pp. 2741-2754. https://doi.org/10.1523/JNEUROSCI.5390-09.2010
Dravid, Shashank M. ; Burger, Pieter B. ; Prakash, Anand ; Geballe, Matthew T. ; Yadav, Roopali ; Le, Phuong ; Vellano, Kimberly ; Snyder, James P. ; Traynelis, Stephen F. / Structural determinants of D-cycloserine efficacy at the NR1/NR2C NMDA receptors. In: Journal of Neuroscience. 2010 ; Vol. 30, No. 7. pp. 2741-2754.
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