PT  - JOURNAL ARTICLE
AU  - Kevin K Ogden
AU  - Stephen F. Traynelis
TI  - Contribution of the M1 Transmembrane Helix and Pre-M1 Region to Positive Allosteric Modulation and Gating of N-Methyl-D-Aspartate Receptors
AID  - 10.1124/mol.113.085209
DP  - 2013 Jan 01
TA  - Molecular Pharmacology
PG  - mol.113.085209
4099  - http://molpharm.aspetjournals.org/content/early/2013/03/01/mol.113.085209.short
4100  - http://molpharm.aspetjournals.org/content/early/2013/03/01/mol.113.085209.full
AB  - N-methyl-D-aspartate (NMDA) receptors are glutamate-gated ion channels whose function is critical for normal excitatory synaptic transmission in the brain and whose dysfunction has been implicated in several neurological conditions. NMDA receptor function is subject to extensive allosteric regulation both by endogenous compounds and by exogenous small molecules. Elucidating the structural determinants and mechanism of action by which allosteric regulators control gating will enhance our understanding of NMDA receptor activation and facilitate the development of novel therapeutics. Here, we investigated the structural determinants for CIQ, a GluN2C/2D-selective positive allosteric modulator. We show that CIQ does not bind to the amino-terminal domain of the NMDA receptor and does not share structural determinants with modulators acting at the agonist-binding domain dimer interface or ion channel pore. Rather, we have identified critical determinants of CIQ modulation in the region near the first transmembrane helix of GluN2D, including in a putative pre-M1 cuff helix that may influence channel gating. We also show that mutations within the GluN2D pre-M1 region alter open probability of the NMDA receptor. These results suggest a novel site of action for potentiation of NMDA receptors by small molecules and implicate the pre-M1 region in NMDA receptor gating.