Article
作者: Garnier-Amblard, Ethel ; Swanger, Sharon A ; Epplin, Matthew P ; Bülow, Pernille ; Fernandez-Cuervo, Gabriela ; Perszyk, Riley E ; Liebeskind, Lanny S ; Gangireddy, Pavan Kumar Reddy ; Traynelis, Stephen F ; Le, Phuong ; Khatri, Alpa ; Shelley, Chris ; Menaldino, David S ; Bassell, Gary J ; Zhang, Jing ; Liotta, Dennis C ; Yuan, Hongjie
Allosteric modulators of ion channels typically alter the transitions rates between conformational states without changing the properties of the open pore. Here we describe a new class of positive allosteric modulators of N-methyl D-aspartate receptors (NMDARs) that mediate a calcium-permeable component of glutamatergic synaptic transmission and play essential roles in learning, memory and cognition, as well as neurological disease. EU1622-14 increases agonist potency and channel-open probability, slows receptor deactivation and decreases both single-channel conductance and calcium permeability. The unique functional selectivity of this chemical probe reveals a mechanism for enhancing NMDAR function while limiting excess calcium influx, and shows that allosteric modulators can act as biased modulators of ion-channel permeation.