Ion Transport from Physics to Physiology: the Missing Rungs in the Ladder

April 3, 2017 to April 5, 2017
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Neurotransmitter funneling optimizes glutamate receptor kinetics

Andrew Plested
Leibniz-Institut für Molekulare Pharmakologie, Germany


Bilobed ligand-binding domains (LBDs), such as those found in ionotropic glutamate receptors (iGluRs), are common architectural elements found in hundreds of small-molecule receptor proteins. Despite their ubiquity, processes essential to receptor activation, such as pathways along which a ligand is guided into its binding site, metastable protein-ligand interactions, and the coupling of ligand binding to protein conformational changes, are poorly understood. Here, we report molecular simulations that show the process of glutamate binding to the AMPA-type iGluR LBD. Charged sidechains on the surface of the LBD are found to metastably bind glutamate and funnel it into its recessed binding pocket. Electrophysiological recordings show that eliminating these transient binding sites reveals a selective and unique kinetic signature of slowed activation and deactivation. These results suggest that preferential binding pathways have evolved to optimize rapid responses of glutamate receptors at central nervous system synapses.