The mammalian ionotropic glutamate receptor family encodes 18 gene products that coassemble to form ligand-gated ion channels containing an agonist recognition site, a transmembrane ion permeation pathway, and gating elements that couple agonist-induced conformational changes to the opening or closing of the permeation pore. Glutamate receptors mediate fast excitatory synaptic transmission in the central nervous system and are localized on neuronal and non-neuronal cells. These receptors regulate a broad spectrum of processes in the brain, spinal cord, retina, and peripheral nervous system. Glutamate receptors are postulated to play important roles in numerous neurological diseases and have attracted intense scrutiny. The description of glutamate receptor structure, including its transmembrane elements, reveals a complex assembly of multiple semiautonomous extracellular domains linked to a pore-forming element with striking resemblance to an inverted potassium channel. In this review we discuss International Union of Basic and Clinical Pharmacology glutamate receptor nomenclature, structure, assembly, accessory subunits, interacting proteins, gene expression and translation, post-translational modifications, agonist and antagonist pharmacology, allosteric modulation, mechanisms of gating and permeation, roles in normal physiological function, as well as the potential therapeutic use of pharmacological agents acting at glutamate receptors.

/pdf/glutamate-receptor-ion-channels-structure-regulation-and-148yts0p6h.pdf

Glutamate Receptor Ion Channels: Structure, Regulation, and Function

Many physiologic effects of l-glutamate, the major excitatory neurotransmitter in the mammalian central nervous system, are mediated via signaling by ionotropic glutamate receptors (iGluRs). These ligand-gated ion channels are critical to brain function and are centrally implicated in numerous psychiatric and neurologic disorders. There are different classes of iGluRs with a variety of receptor subtypes in each class that play distinct roles in neuronal functions. The diversity in iGluR subtypes, with their unique functional properties and physiologic roles, has motivated a large number of studies. Our understanding of receptor subtypes has advanced considerably since the first iGluR subunit gene was cloned in 1989, and the research focus has expanded to encompass facets of biology that have been recently discovered and to exploit experimental paradigms made possible by technological advances. Here, we review insights from more than 3 decades of iGluR studies with an emphasis on the progress that has occurred in the past decade. We cover structure, function, pharmacology, roles in neurophysiology, and therapeutic implications for all classes of receptors assembled from the subunits encoded by the 18 ionotropic glutamate receptor genes. SIGNIFICANCE STATEMENT: Glutamate receptors play important roles in virtually all aspects of brain function and are either involved in mediating some clinical features of neurological disease or represent a therapeutic target for treatment. Therefore, understanding the structure, function, and pharmacology of this class of receptors will advance our understanding of many aspects of brain function at molecular, cellular, and system levels and provide new opportunities to treat patients.

Structure, Function, and Pharmacology of Glutamate Receptor Ion Channels.

Although being a physiologically important excitatory neurotransmitter, glutamate plays a pivotal role in various neurological disorders including ischemic neurological diseases. Its level is increased during cerebral ischemia with excessive neurological stimulation causing the glutamate-induced neuronal toxicity, excitotoxicity, and this is considered the triggering spark in the ischemic neuronal damage. The glutamatergic stimulation will lead to rise in the intracellular sodium and calcium, and the elevated intracellular calcium will lead to mitochondrial dysfunction, activation of proteases, accumulation of reactive oxygen species and release of nitric oxide. Interruption of the cascades of glutamate-induced cell death during ischemia may provide a way to prevent, or at least reduce, the ischemic damage. Various therapeutic options are suggested interrupting the glutamatergic pathways, e.g., inhibiting the glutamate synthesis or release, increasing its clearance, blocking of its receptors or preventing the rise in intracellular calcium. Development of these strategies may provide future treatment options in the management of ischemic stroke.

https://static.springer.com/sgw/documents/1377406/application/pdf/Neuro+Sciences_Oscars_%235.pdf

The role of glutamate in neuronal ischemic injury: the role of spark in fire

Basic Concepts Electricity, nerves, batteries: A short history Clay M. Armstrong Ion selectivity and conductance Dorothy M. Kim, Jason G. McCoy, and Crina M. Nimigean Basic mechanisms of voltage sensing Sandipan Chowdhury and Baron Chanda Ligand-dependent gating mechanism William N. Zagotta Mechanosensitive channels and their emerging gating mechanisms Sergei Sukharev and Andriy Anishkin Ion Channel Methods Patch clamping and single-channel analysis Leon D. Islas Models of ion channel gating Frank T. Horrigan and Toshinori Hoshi Utilizing Markov chains to model ion channel sequence variation and kinetics Anthony Fodor Investigation of ion channel structure using fluorescence spectroscopy Rikard Blunck A practical guide to solving the structure of an ion channel protein Tahmina Rahman and Declan A. Doyle Structural study of ion channels by cryo-electron microscopy Qiu-Xing Jiang and Liang Shi Rosetta structural modeling Vladimir Yarov-Yarovoy Genetic methods for studying ion channel function in physiology and disease Andrea L. Meredith Ion channel inhibitors Jon Sack and Kenneth S. Eum High-throughput methods for ion channels Haibo Yu and Min Li Ion Channel Families Voltage-gated sodium channels William A. Catterall BK channels Huanghe Yang and Jianmin Cui Inward rectifying potassium channels Monica Sala-Rabanal and Colin G. Nichols Two-pore domain potassium channels Leigh D. Plant and Steve A.N. Goldstein KCNQ channels Nikita Gamper and Mark S. Shapiro Ionotropic glutamate receptors Andrew Plested 5-HT3 receptors Sarah C.R. Lummis GABAA receptors Trevor G. Smart Cyclic nucleotide-gated channels Michael D. Varnum and Gucan Dai Acid-sensing ion channels Cecilia Canessa Degenerin/ENaC channels James D. Stockand TRPC channels Jin-Bin Tian, Dhananjay Thakur, Yungang Lu, and Michael X. Zhu TRPV channels Sharona E. Gordon TRPM channels David D. McKemy TRPML channels Qiong Gao, Xiaoli Zhang, and Haoxing Xu CLC chloride channels and transporters Giovanni Zifarelli and Michael Pusch Ca-activated chloride channels Xiuming Wong and Lily Jan Store-operated CRAC channels Murali Prakriya Ion Channel Regulation Mechanism of G-protein regulation of K+ channels Rahul Mahajan and Diomedes E. Logothetis Calmodulin regulation of voltage-gated calcium channels and beyond Manu Ben-Johny and David T. Yue Phosphorylation of voltage-gated ion channels James S. Trimmer and Hiroaki Misonou Alternative splicing Andrea L. Meredith Single transmembrane regulatory subunits of voltage-gated potassium channels William R. Kobertz and Anatoli Lvov Ion Channel Physiology and Diseases Ion channels of the heart Donald M. Bers and Eleonora Grandi Ion channels in pain J.P. Johnson, Jr. CLC-related proteins in diseases Allan H. Bretag and Linlin Ma Cystic fibrosis and the CFTR anion channel Yoshiro Sohma and Tzyh-Chang Hwang Drugs targeting ion channels KeWei Wang Index

Handbook of ion channels

The fate of medications evaluated for ischemic stroke pharmacotherapy over the period 1995-2015.

Background and Purpose: ZK 200775 is a selective competitive AMPA receptor antagonist. It has demonstrated neuroprotective efficacy in experimental models of stroke and tolerability

The AMPA antagonist ZK 200775 in patients with acute ischaemic stroke: a double-blind, multicentre, placebo-controlled safety and tolerability study

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The AMPA antagonist ZK 200775 in patients with acute ischaemic stroke: a double-blind, multicentre, placebo-controlled safety and tolerability study