Coupled Control of Desensitization and Gating by the Ligand Binding Domain of Glutamate Receptors

The kinetics of ligand gated ion channels are tuned to permit diverse roles in cellular signaling. To follow high-frequency excitatory synaptic input, postsynaptic AMPA-type glutamate receptors must recover rapidly from desensitization. Chimeras between AMPA and the related kainate receptors demonstrate that the ligand binding domains alone control the lifetime of the desensitized state. Mutation of nonconserved amino acids in the lower lobe (domain 2) of the ligand binding domain conferred slow recovery from desensitization on AMPA receptors, and fast recovery on kainate receptors. Single-channel recordings and a correlation between the rate of deactivation and the rate of recovery across panels of mutant receptors revealed that domain 2 also controls ion channel gating. Our results demonstrate that the same mechanism that ensures fast recovery also sharpens the response of AMPA channels to synaptically released glutamate. ► Glutamate receptor ligand binding domains alone set the desensitized state lifetime ► Distributed sites control recovery rate in AMPA and kainate receptors ► Kinetics of channel gating and recovery from desensitization are highly correlated ► In AMPARs, kinetic tuning favors increased signaling precision and bandwidth Glutamate receptor ion channels have a common molecular architecture but disparate kinetic properties. Carbone and Plested reveal that glutamate-binding domains control recovery from desensitization and gating in AMPA and kainate receptors, tuning AMPA receptors for precise, high-frequency synaptic transmission.