RT Journal Article
SR Electronic
T1 AMPA Receptor Binding Cleft Mutations That Alter Affinity, Efficacy, and Recovery from Desensitization
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 3752
OP 3762
DO 10.1523/JNEUROSCI.0188-05.2005
VO 25
IS 15
A1 Antoine Robert
A1 Neali Armstrong
A1 J. Eric Gouaux
A1 James R. Howe
YR 2005
UL http://www.jneurosci.org/content/25/15/3752.abstract
AB Glutamate binds to AMPA receptors within a deep cleft between two globular protein domains (domains 1 and 2). Once glutamate binds, the cleft closes, and agonist-bound structures of the isolated ligand binding core suggest that closure of the binding cleft is sufficiently complete that it essentially prevents ligand dissociation. There is also considerable evidence supporting the view that cleft closure is the initial conformational change that triggers receptor activation and desensitization, and it has been clearly demonstrated that there is a correlation between the degree of cleft closure and agonist efficacy. It is unknown, however, whether the stability of binding cleft closure also influences receptor-channel properties. The crystallographic structures indicate that closed-cleft conformations are stabilized by the formation of hydrogen bonds that involve amino acid side chains of residues in domains 1 and 2. We show here that mutations that disrupt one such cross-cleft hydrogen bond (in the AMPA receptor subunit GluR2) decrease both agonist affinity and efficacy. The same mutations also hasten recovery from desensitization. We conclude that the stability of binding cleft closure has a significant impact on AMPA receptor function and is a major determinant of the apparent affinity of agonists. The results suggest that the stability of cleft closure has been tuned so that glutamate dissociates as rapidly as possible yet remains a full agonist.