An Ionic Switch in the Ligand-Binding Domain of Non-NMDA Receptors

Abstract

The ionotropic glutamate receptors (iGluRs), activated by the amino acid L-glutamate, account for the vast majority of excitatory neurotransmission in the central nervous system. Given their centrality to the nervous system, it is not surprising that these receptors have been linked to various neurological disorders including epilepsy, Alzheimer's and Parkinson's disease. Based on their sequence, pharmacological properties and function, iGluRs are classified primarily into three subtypes, namely amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), kainate (KA), and N-methyl-D-aspartate (NMDA) receptors.Previously we have reported the identification of a potential ionic switch, or latch, located within the hinge region of non-NMDA receptors. Here we describe extensive molecular dynamics simulations to explore the conformational behaviour of the ionic switch and its influence on the closure or opening of the ligand-binding domain. The position of the switch appears to directly control the conformation of the ligand-binding domain. We discuss the results with respect to the general mechanism of how different ligands are able to induce the same mechanism of domain closure.