Structural Insights into Function of Ionotropic Glutamate Receptors
Published on 08.16.2022 in Biochemistry (Moscow), Supplement Series A: Membrane and Cell Biology
M. V. Yelshanskaya and A. I. Sobolevsky
Ionotropic glutamate receptors (iGluRs) mediate fast excitatory neurotransmission. They are implicated in nervous system development and function, while their dysfunction is associated with neurological and psychiatric disorders. In this review, we describe recent progress in structural studies of iGluRs and how crystal and cryo-EM structures helped determining the principles of iGluR architecture and assembly, and the mechanisms of activation, desensitization and regulation by auxiliary subunits, positive and negative allosteric modulators, and ion channel blockers. The new structural insights facilitate better understanding of iGluR physiological and pathophysiological roles in functioning of the central nervous system and provide valuable information for structure-based drug design.
This article was published in thematic issue dedicated to the 100th Anniversary of B. I. Khodorov, an outstanding Soviet/Russian neurophysiologist who made an enormous contribution to the study of excitable biological membranes, to the biophysics and physiology of the nervous system.
«Several generations of biophysicists, physiologists, and neurobiologists learned from Boris Israelievich Khodorov’s monographs and textbooks. Together with his students and colleagues, he created high-quality electrophysiological facilities for recording of electrical signals in the Ranvier node of isolated nerve fibers and also developed other original experimental models for studying the excitability of ion channels. Using these models, the mechanisms of action of various anesthetics and other substances on the generation of action potentials were investigated. The parameters of activation and inactivation of sodium currents were analyzed using mathematical models, primarily the Hodgkin–Huxley equations. The results of these studies have been included in textbooks, books and manuals on biophysics and physiology of the nervous system. The assumptions made in the early works of B.I. Khodorov that local anesthetics and antiarrhythmic drugs pass to the pore of the ion channel through the hydrophobic pathway of the lipid membrane received convincing confirmation and evidence half a century later, after obtaining the crystal structure of the sodium channel in 2011. Pioneering studies of B.I. Khodorov on the dysregulation of calcium homeostasis of brain neurons during glutamate receptor hyperstimulation, as well as elucidating the role of mitochondria in brain cell neurotoxicity, received wide international recognition». (Exсerption from «A long-liver and Knight of Science. To the 100th Anniversary of B. I. Khodorov» by P. Bregestovski).