Structural Mechanism of Glutamate Receptor Activation and Desensitization
Understanding the structural basis of the transition from closed to active and desensitized conformations is central to deciphering the function of ionotropic glutamate receptors NMDA receptors, AMPA receptors, delta receptors, and kainate receptors as mediators of excitatory synaptic transmission in the central nervous system. Ligand binding at the receptor’s extracellular surface opens the cation-selective pore, and channel opening is followed by desensitization, which closes the pore. In this study, we use cryo-electron microscopy to visualize the AMPA receptor GluA2 and the kainate receptor GluK2 in several functional states resting, open and desensitized. Based on theses structures, we propose a molecular model for the gating cycle of glutamate receptors.
Ionotropic glutamate receptors are ligand-gated ion channels that mediate excitatory synaptic transmission in the vertebrate brain. To gain a better understanding of how structural changes gate ion flux across the membrane, we trapped rat AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) and kainate receptor subtypes in their major functional states and analysed the resulting structures using cryo-electron microscopy. We show that transition to the active state involves a 'corkscrew' motion of the receptor assembly, driven by closure of the ligand-binding domain. Desensitization is accompanied by disruption of the amino-terminal domain tetramer in AMPA, but not kainate, receptors with a two-fold to four-fold symmetry transition in the ligand-binding domains in both subtypes. The 7.6 Å structure of a desensitized kainate receptor shows how these changes accommodate channel closing. These findings integrate previous physiological, biochemical and structural analyses of glutamate receptors and provide a molecular explanation for key steps in receptor gating.