title: A subunit-selective potentiator of NR2C- and NR2D-containing NMDA receptors.
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.
authors.affiliation: Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: Praseeda
authors.initials: P
authors.lastname: Mullasseril
authors.forename: Kasper B
authors.initials: KB
authors.lastname: Hansen
authors.forename: Katie M
authors.initials: KM
authors.lastname: Vance
authors.forename: Kevin K
authors.initials: KK
authors.lastname: Ogden
authors.forename: Hongjie
authors.initials: H
authors.lastname: Yuan
authors.forename: Natalie L
authors.initials: NL
authors.lastname: Kurtkaya
authors.forename: Rose
authors.initials: R
authors.lastname: Santangelo
authors.forename: Anna G
authors.initials: AG
authors.lastname: Orr
authors.forename: Phuong
authors.initials: P
authors.lastname: Le
authors.forename: Kimberly M
authors.initials: KM
authors.lastname: Vellano
authors.forename: Dennis C
authors.initials: DC
authors.lastname: Liotta
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Traynelis
mesh_terms: D000818:Animals; D018698:Glutamic Acid / Q000378:metabolism; D005998:Glycine / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*
chemical_list: C432823:NR2C NMDA receptor; C464436:NR2D NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D005998:Glycine