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

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

Published In Nat Commun, (2010)

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(1H)-yl)methanone) enhances receptor responses two-fold with an EC(50) of 3 μM by increasing channel opening frequency without altering mean open time or EC(50) 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.

PubMed ID: 20981015 Exiting the NIEHS site

MeSH Terms: Animals; Glutamic Acid/metabolism; Glycine/metabolism; HEK293 Cells; Humans; Patch-Clamp Techniques; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate/metabolism*

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