The 140th Annual Meeting of the Pharmaceutical Society of Japan (Kyoto)

Presentation information

Symposium

[S07] Understanding neurological diseases and developing therapeutics focusing on the modulation of the glutamate nervous system

Thu. Mar 26, 2020 9:00 AM - 11:00 AM [Room U] Swan (1F)

Organizers: Toshiaki Kume (Grad Sch Pharm Sci, Univ Toyama), Satoshi Deyama (Inst Med Pharm Health Sci, Kanazawa Univ)

9:02 AM - 9:42 AM

[S07-1] Allosteric modulation of glutamate receptors

Riley E Perszyk1, Sharon A Swanger1,2, Chris Shelley1,3, Alpa Khatri1, Gabriela Fernandez-Cuervo4, Matthew P. Epplin4, Jing Zhang1, Phuong Le1, Pernille Bülow5,6, Ethel Garnier-Amblard4, Pavan Kumar Reddy Gangireddy4, Gary J. Bassell6, Hongjie Yuan1, David S. Menaldino4, Dennis C. Liotta4, Lanny S. Liebeskind4, ○Stephen F. Traynelis1 (1. Dept Pharmacol Chem Biol, Emory Univ, Sch Med, 2. Virginia Tech Carilion Res Inst, 3. Dept Biol, Univ South, 4. Dept Chem, Emory Univ, 5. Dept Physiol, Emory Univ, 6. Dept Cell Biol, Emory Univ)

NMDA receptors (NMDARs) are ligand-gated ion channels that are tetrameric assemblies of 2 glycine-binding GluN1 subunits and 2 glutamate-binding GluN2 subunits. NMDARs respond to synaptically-released glutamate by producing a slow inward current mediated by Na+ and Ca2+. We hypothesize that 3 gating elements control opening of the pore, including 9 conserved residues (SYTANLAAF) that comprise the extracellular end of the M3 transmembrane helix, a short helix that is parallel to the plane of the membrane and precedes the M1 transmembrane helix, and a linker preceding the M4 transmembrane helix. We identified several allosteric modulators that act at the pre-M1 region, one of which reduces single channel conductance, an effect not previously observed for NMDAR modulators. For example, EU1622-14 reduces single channel conductance of NMDARs on cultured cortical neurons from 52, 44 pS in vehicle to 42, 35, and 28 pS (n= 7 outside out patches, Vm -80 mV). EU1622-14 also reduced the relative permeability of Ca2+ to Na+ for recombinant GluN1/GluN2A and GluN1/GluN2B receptors by more than 2-fold (p<0.05, ANOVA). This is the first example of an exogenous drug-like allosteric modulator that can interact with the NMDAR to alter the relative permeability of ions, which has important biophysical implications. In addition, the precedent that Ca2+ permeability can be controlled pharmacologically creates a new potential therapeutic target with intriguing possibilities.