Kinetic basis of partial agonism at NMDA receptors

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Abstract
The authors propose a mechanism of partial agonism, showing that partial agonists of both GluN1 and GluN2 NMDA receptor subunits have similar effects on the NMDA receptor activation reaction and they increase the height of all energy barriers during NMDA receptor activation. This contrasts with the localized effects observed for pentameric ligand-gated channels. 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. We found that low-efficacy agonists acting at either the glycine-binding or the glutamate-binding NMDA receptor subunits 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 found 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 that have been observed for pentameric ligand-gated channels and may represent a previously unknown mechanism by which partial agonists reduce receptor activity.

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