Journal
NATURE COMMUNICATIONS
Volume 1, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms1085
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Funding
- NIH-NINDS [NS036654, NS065371]
- Lundbeck Foundation
- Villum Kann Rasmussen Foundation
- Michael J Fox Foundation
- Emory University Research Committee
- Georgia Tech/Emory Center for Engineering of Living Tissue
- Atlanta Clinical and Translational Science Institute
- Pfizer
- NIH-NIGMS [GM008602]
- NIH-NIDA [DA01504006]
- NIH-NIEHS [ES012870]
- Emory Chemistry Biology Discovery Center
- Robert P. Apkariam Integrated Electron Microscopy Emory University Core
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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 EC50 of 3 mu M 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.
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