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Author Notes:

Corresponding Author: Dr. Stephen Traynelis, Dept Pharmacology, Emory University School of Medicine, Rollins Research Center, 1510 Clifton Road, Atlanta, GA 30322-3090, Tel 404 727 0357, Fax 404 727 0365, strayne@emory.edu

Author Contributions PM, KBH, KMV, KKO, HY, NLK, AGO, PL, KMV, SFT all participated in identification of the initial class of tetrahydroisoquinoline potentiators, as well as recording and analysis of the data. RS, DCL, SFT participated in determination of the structure activity relationship leading to identification of CIQ. All authors participated in writing the manuscript.


Research Funding:

This work was supported by the NIH-NINDS (NS036654, NS065371 SFT), the Lundbeck Foundation (KBH), the Villum Kann Rasmussen Foundation (KBH), the Michael J Fox Foundation (SFT), the Emory University Research Committee (SFT), the Georgia Tech/Emory Center for Engineering of Living Tissue and the Atlanta Clinical and Translational Science Institute (SFT), a Research Grant from Pfizer, Inc. (SFT), NIH-NIGMS training grant GM008602 (KKO), NIH-NIDA training grant DA01504006 (KMV), NIH-NIEHS training grant ES012870 (KMV), the Emory Chemistry Biology Discovery Center, and the Robert P. Apkariam Integrated Electron Microscopy Emory University Core.

A subunit-selective potentiator of NR2C- and NR2D-containing NMDA receptors

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Journal Title:

Nature Communications


Volume 1


, Pages 90-90

Type of Work:

Article | Post-print: After Peer Review


NMDA receptors are tetrameric complexes of NR1 and NR2A-D subunits that mediate excitatory synaptic transmission and play a role in neurological disorders. We have identified a novel subunit-selective potentiator of NMDA receptors containing the NR2C or NR2D subunit, which could allow selective modification of circuit function in regions expressing NR2C/D subunits. The substituted tetrahydroisoquinoline CIQ enhances receptor responses two-fold with an EC50 of 3 μM by increasing channel opening frequency without altering mean open time or EC50 values for glutamate or glycine. The actions of CIQ depend on a single residue in the M1 region (NR2D Thr592) and the linker between the amino terminal domain and agonist binding domain. CIQ potentiates native NR2D-containing NMDA receptor currents from subthalamic neurons. Our identification of a subunit-selective NMDA receptor modulator reveals a new class of pharmacological tools with which to probe the role of NR2C- and NR2D-containing NMDA receptors in brain function and disease.

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© 2010 Macmillan Publishers Limited. All rights reserved.

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