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

Praseeda Mullasseril, Kasper B. Hansen, Katie M. Vance, Kevin K. Ogden, Hongjie Yuan, Natalie L. Kurtkaya, Rose Santangelo, Anna G. Orr, Phuong Le, Kimberly M. Vellano, Dennis C. Liotta, Stephen F. Traynelis

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130 Scopus citations

Abstract

NMDA receptors are tetrameric complexes of NR1 and NR2A-D subunits that mediate excitatory synaptic transmission and have a role in neurological disorders. In this article, we identify 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 (3-chlorophenyl)(6,7-dimethoxy-1-((4- methoxyphenoxy)methyl)-3,4-dihydroisoquinolin-2(1 H)-yl)methanone) 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 on the linker between the N-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.

Original languageEnglish
Article number90
JournalNature Communications
Volume1
Issue number7
DOIs
StatePublished - 2010

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