A subunit-selective potentiator of NR2C- and NR2D-containing NMDA receptors.
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.
Mullasseril
Praseeda
P
Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Hansen
Kasper B
KB
Vance
Katie M
KM
Ogden
Kevin K
KK
Yuan
Hongjie
H
Kurtkaya
Natalie L
NL
Santangelo
Rose
R
Orr
Anna G
AG
Le
Phuong
P
Vellano
Kimberly M
KM
Liotta
Dennis C
DC
Traynelis
Stephen F
SF
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*
C432823:NR2C NMDA receptor; C464436:NR2D NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D005998:Glycine