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 and Stephen F. Traynelis ()
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Praseeda Mullasseril: Emory University School of Medicine
Kasper B. Hansen: Emory University School of Medicine
Katie M. Vance: Emory University School of Medicine
Kevin K. Ogden: Emory University School of Medicine
Hongjie Yuan: Emory University School of Medicine
Natalie L. Kurtkaya: Emory University School of Medicine
Rose Santangelo: Emory University
Anna G. Orr: Emory University School of Medicine
Phuong Le: Emory University School of Medicine
Kimberly M. Vellano: Emory University School of Medicine
Dennis C. Liotta: Emory University
Stephen F. Traynelis: Emory University School of Medicine

Nature Communications, 2010, vol. 1, issue 1, 1-8

Abstract: 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.

Date: 2010
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DOI: 10.1038/ncomms1085

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