Kinetic basis of partial agonism at NMDA receptors

Abstract

Activation of ligand-gated channels is initiated by the binding of small molecules at extracellular sites and culminates with the opening of a membrane-embedded pore. To investigate how perturbations at ligand-binding domains influence the gating reaction, we examined current traces recorded from individual NMDA receptors in the presence of several subunit-specific partial agonists. Here we show that low-efficacy agonists acting at either the GluN1 or the GluN2A subunit had very similar effects on the receptor’s activation reaction, possibly reflecting a high degree of coupling between the two subunit-types during gating. In addition, we demonstrate that partial agonists increased the height of all energy barriers encountered by NMDA receptors during activation. This result stands in sharp contrast to the localized effects observed for pentameric ligand-gated channels and may represent a novel mechanism by which partial agonists reduce receptor activity.