Inhibition mechanism of AMPA receptors by the pore blocker memantine.

Abstract

Fast excitatory synaptic transmission in the mammalian central nervous system is mediated by AMPA-type ionotropic glutamate receptors. AMPA receptors co-assemble with auxiliary proteins, such as transmembrane AMPA receptor regulatory proteins (TARPs), cornichons, cysteine knot proteins and GSG1; which regulate AMPAR assembly, trafficking, gating, and pharmacology. TARPs are the most studied AMPAR auxiliary proteins for their role in the synaptic plasticity. The coupling between AMPA and TARPs change their kinetic and pharmacology properties. Here we show that in the presence of TARPs GluA2 receptors are inhibited by memantine. Memantine inhibition is dependent on charge at site 607, glutamine to arginine mutation showing a larger inhibition by memantine relative to the that GluA2(R) and the GluA2(Q). The inhibition by memantine is activity- and voltage-dependent, suggesting a pore block mechanism.