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Glutamate Receptor Ion Channels: Structure, Regulation, and Function

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0031-6997/10/6203-405–496$20.00 PHARMACOLOGICAL REVIEWS Vol. 62, No. 3 U.S. Government work not protected by U.S. copyright 2451/3592788 Pharmacol Rev 62:405–496, 2010 Printed in U.S.A. ASSOCIATE EDITOR: DAVID SIBLEY Glutamate Receptor Ion Channels: Structure, Regulation, and Function Stephen F. Traynelis, Lonnie P. Wollmuth, Chris J. McBain, Frank S. Menniti,1 Katie M. Vance, Kevin K. Ogden, Kasper B. Hansen, Hongjie Yuan, Scott J. Myers, and Ray Dingledine Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia (S.F.T., K.M.V., K.K.O., K.B.H., H.Y., S.J.M., R.D.); Department of Neurobiology and Behavior & Center for Nervous System Disorders, Stony Brook University, Stony Brook, New York (L.P.W.); Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland (C.J.M.); and cyclicM LLC, Mystic, Connecticut (F.S.M.) Abstract ................................................................................ 406 I. Introduction and nomenclature ........................................................... 407 II. Structure ............................................................................... 407 A. Subunit organization and quaternary structure ......................................... 407 B. Subunit stoichiometry ................................................................ 409 C. Receptor assembly and trafficking ..................................................... 411 D. The extracellular ligand binding domain................................................ 412 E. The extracellular amino-terminal domain ............................................... 414 F. The transmembrane domain........................................................... 415 G. The intracellular carboxyl-terminal domain and protein binding partners .................. 415 H. Transmembrane ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor regulatory proteins and other auxiliary subunits ........................................ 418 III. Regulation of transcription and translation................................................. 419 A. ␣-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors .......................... 419 1. Gria1............................................................................. 419 2. Gria2............................................................................. 420 3. Gria3 and Gria4................................................................... 421 B. Kainate receptors Grik1 to Grik5 ...................................................... 421 C. N-Methyl-D-aspartate receptors ........................................................ 421 1. Grin1 ............................................................................ 421 2. Grin2a ........................................................................... 422 3. Grin2b ........................................................................... 422 4. Grin2c, Grin2d, Grin3a, and Grin3b ................................................. 423 D. Translational control of glutamate receptors ............................................ 424 IV. Post-translational regulation.............................................................. 425 A. ␣-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and kainate receptor phosphorylation ...................................................................... 425 B. N-Methyl-D-aspartate and ␦ receptor phosphorylation .................................... 427 C. Other post-translational modifications of glutamate receptors............................. 429 D. Proteolysis of glutamate receptors...................................................... 430 V. Agonist and antagonist pharmacology ..................................................... 431 A. ␣-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, kainate, and ␦ receptor agonists ..... 431 B. N-Methyl-D-aspartate receptor agonists................................................. 434 C. ␣-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and kainate receptor competitive antagonists .......................................................................... 437 D. N-Methyl-D-aspartate receptor competitive antagonists .................................. 439 Address correspondence to: Dr. Stephen Traynelis, Dept Pharmacology, Emory University School of Medicine, Rollins Research Center, 1510 Clifton Road, Atlanta GA 30322-3090. E-mail: [email protected] 1Current affiliation: Mnemosyne Pharmaceuticals, Inc., Providence, Rhode Island. This article is available online at http://pharmrev.aspetjournals.org. doi:10.1124/pr.109.002451. 405 406 TRAYNELIS ET AL. E. Noncompetitive antagonists ........................................................... 440 F. Uncompetitive antagonists ............................................................ 443 VI. Allosteric regulation ..................................................................... 445 A. Positive and negative allosteric modulators ............................................. 445 B. Divalent ions ........................................................................ 447 C. Monovalent ions...................................................................... 448 D. Protons.............................................................................. 449 E. Polyamines .......................................................................... 449 F. Neurosteroids ........................................................................ 450 G. Fatty acids .......................................................................... 450 H. Other allosteric modulators ........................................................... 450 VII. Molecular determinants of gating ......................................................... 450 A. Time course of glutamate receptor activation and deactivation ............................ 450 B. Mechanisms linking agonist binding to channel gating ................................... 451 C. Molecular determinants and mechanisms of partial agonism.............................. 453 D. Molecular determinants and mechanisms of gating ...................................... 455 E. Molecular determinants of desensitization .............................................. 457 VIII. Molecular determinants of ion permeation and block ........................................ 458 A. Nature of the ion permeation pathway ................................................. 458 B. Mechanisms of ion permeation......................................................... 460 C. Voltage-dependent channel block by endogenous ions .................................... 462 IX. Role in synaptic function and plasticity .................................................... 463 A. Synaptic ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors .................. 463 B. Synaptic kainate receptors ............................................................ 464 C. Synaptic and extrasynaptic N-Methyl-D-aspartate receptors .............................. 465 D. Synaptic plasticity.................................................................... 466 1. N-Methyl-D-aspartate receptors ..................................................... 466 2. ␣-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors ....................... 467 X. Therapeutic potential .................................................................... 467 A. Glutamate receptor antagonists and the prevention of acute neuronal death ............... 467 B. The next generation ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and kainate receptor antagonists .................................................................. 469 C. The next generation N-methyl-D-aspartate receptor antagonists........................... 469 D. N-Methyl-D-aspartate antagonists...................................................... 470 1. Neuropathic pain .................................................................. 470 2. Major depression .................................................................. 471 3. Parkinson’s disease ................................................................ 471 E. ␣-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and kainate receptor potentiation .... 471 F. N-Methyl-D-aspartate receptor potentiation ............................................. 472 XI. Conclusions ............................................................................. 473 Acknowledgments ....................................................................... 474 References .............................................................................. 474 Abstract——The mammalian ionotropic glutamate re- ceptor structure, including its transmembrane elements, ceptor family encodes 18 gene products that coassemble to reveals a complex assembly of multiple semiautonomous form ligand-gated ion channels containing an agonist rec- extracellular domains linked to a pore-forming element ognition site, a transmembrane ion permeation pathway, with striking resemblance to an inverted potassium chan- and gating elements that couple agonist-induced confor- nel. In this review we discuss International Union of Basic mational changes to the opening or closing of the perme- and Clinical Pharmacology glutamate receptor nomencla- ation pore. Glutamate receptors mediate fast excitatory ture, structure, assembly, accessory subunits, interacting synaptic transmission in the central nervous system and proteins, gene expression and translation, post-transla- are localized on neuronal and non-neuronal cells.
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