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

• Authors: Praseeda Mullasseril, Emory University; Kasper B. Hansen, Emory University; Katie M. Vance, Emory University; Kevin K. Ogden, Emory University; Hongjie Yuan, Emory University; Natalie L. Kurtkaya, Emory University; Rose Santangelo, Emory University; Anna G. Orr, Emory University; Phuong Le, Emory University; Kimberly M. Vellano, Emory University; Dennis C Liotta, Emory University; Stephen F. Traynelis, Emory University
• Journal Title: Nature Communications
• Volume: Volume 1
• Publisher: Nature Research (part of Springer Nature): Fully open access journals | 2010-10-05, Pages 90-90
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1038/ncomms1085
• Subjects: Chemistry, Biochemistry; Health Sciences, Pharmacology; Biology, Neuroscience

Abstract

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.