The Glutamate Receptor Ion Channels
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0031-6997/99/5101-0007$03.00/0 PHARMACOLOGICAL REVIEWS Vol. 51, No. 1 Copyright © 1999 by The American Society for Pharmacology and Experimental Therapeutics Printed in U.S.A. The Glutamate Receptor Ion Channels RAYMOND DINGLEDINE,1 KARIN BORGES, DEREK BOWIE, AND STEPHEN F. TRAYNELIS Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia This paper is available online at http://www.pharmrev.org I. Introduction ............................................................................. 8 II. Gene families ............................................................................ 9 III. Receptor structure ...................................................................... 10 A. Transmembrane topology ............................................................. 10 B. Subunit stoichiometry ................................................................ 10 C. Ligand-binding sites located in a hinged clamshell-like gorge............................. 13 IV. RNA modifications that promote molecular diversity ....................................... 15 A. Alternative splicing .................................................................. 15 B. Editing of AMPA and kainate receptors ................................................ 17 V. Post-translational modifications .......................................................... 18 A. Phosphorylation of AMPA and kainate receptors ........................................ 18 B. Serine/threonine phosphorylation of NMDA receptors ................................... 19 C. Tyrosine phosphorylation of NMDA receptors........................................... 20 D. Glycosylation, proteolysis, and covalently bound lipids................................... 21 VI. Receptor activation and desensitization ................................................... 22 A. Agonists ............................................................................ 22 B. Competitive antagonists: new developments ............................................ 23 C. Noncompetitive antagonists........................................................... 23 D. Uncompetitive blockers............................................................... 24 E. Antagonists with unknown mechanism ................................................ 25 F. Glutamate receptor kinetics........................................................... 25 G. Molecular determinants of AMPA receptor deactivation and desensitization ............... 27 H. Molecular determinants of kainate receptor deactivation and desensitization .............. 28 I. Molecular determinants of NMDA receptor deactivation and desensitization ............... 28 VII. Endogenous allosteric modulators......................................................... 30 A. Extracellular zinc .................................................................... 30 B. Reduction and oxidation of extracellular cysteine residues ............................... 31 C. Extracellular protons................................................................. 32 D. Extracellular polyamines ............................................................. 33 VIII. Molecular determinants of ion permeation ................................................. 34 A. Pore diameter ....................................................................... 34 B. Unitary sublevel conductances ........................................................ 35 C. Ionic selectivity ...................................................................... 38 IX. Molecular determinants of channel block .................................................. 39 A. External Mg21 block of NMDA receptors ............................................... 39 B. Internal Mg21 block of NMDA receptors ............................................... 41 C. Internal polyamine block of AMPA and kainate receptors ................................ 41 X. Molecular composition of the pore ........................................................ 43 A. Outer vestibules ..................................................................... 43 B. Narrow constriction and selectivity filter ............................................... 43 XI. Association of glutamate receptors with intracellular proteins ............................... 43 A. AMPA receptors ..................................................................... 44 B. NMDA receptors: signaling molecules and proteins lacking PDZ domains ................. 45 C. NMDA receptors: PDZ domain-containing proteins ...................................... 45 D. Kainate receptors .................................................................... 47 1 Address for correspondence: Raymond Dingledine, Department of Pharmacology, Emory University School of Medicine, 1510 Clifton Road, Atlanta, GA 30322. E-mail: [email protected] 7 8 DINGLEDINE ET AL. XII. Genetic regulation of receptor expression .................................................. 47 A. Transcriptional control ............................................................... 47 B. Translational control ................................................................. 48 XIII. Therapeutic potential: clinical trials ...................................................... 48 A. Ischemic stroke ...................................................................... 49 B. Neuropathic pain .................................................................... 49 C. Parkinson’s disease .................................................................. 50 D. Cognitive enhancement............................................................... 50 XIV. Outlook ................................................................................ 50 XV. Acknowledgments ....................................................................... 51 XVI. References.............................................................................. 51 I. Introduction resorption (Chenu et al., 1998; Patton et al., 1998) raise The ionotropic glutamate receptors are ligand-gated the possibilities that antagonists restricted to the pe- ion channels that mediate the vast majority of excitatory riphery might find uses in the treatment of diabetes and neurotransmission in the brain. The cloning of cDNAs osteoporosis. Moreover, there is evidence for the pres- encoding glutamate receptor subunits, which occurred ence of NMDA and non-NMDA receptors in small, un- mainly between 1989 and 1992 (Hollmann and Heine- myelinated sensory nerve terminals in the skin (Ault mann, 1994), stimulated this field like no other event and Hildebrand, 1993; Carlton et al., 1995). Subcutane- since the recognition in the early 1980s that the N- ous injection of as little as 300 pmol of 6-cyano-7-nitro- 2 methyl-D-aspartate (NMDA) receptor antagonist, quinoxaline-2,3-dione (CNQX) or 30 pmol of MK-801 D-AP5, has neuroprotective and anticonvulsant proper- produced analgesia for a subsequent injection of forma- ties (reviewed by Choi, 1998; Dingledine et al., 1990), lin into the same site. These findings raise the possibil- and that calcium entry through glutamate receptor ity that peripheral glutamate receptors residing on channels plays important roles in development and in nerve terminals in the skin may be a target for certain forms of synaptic plasticity that may underlie higher forms of pain associated with inflammation. NMDA re- order processes such as learning and memory (Maren ceptor antagonists can also reduce histamine secretion and Baudry, 1995; Asztely and Gustafsson, 1996). These from mast cells collected from the rat peritoneal cavity earlier findings implicated NMDA receptors in a variety (Purcell et al., 1996), and NMDA depolarizes and ele- 21 of neurologic disorders that include epilepsy, ischemic vates intracellular Ca in mouse taste receptor cells in brain damage, and, more speculatively, neurodegenerative taste buds (Hayashi et al., 1996). Numerous ionotropic disorders such as Parkinson’s and Alzheimer’s diseases, glutamate receptor subunits appear to be expressed by Huntington’s chorea, and amyotrophic lateral sclerosis. cardiac ganglia, but their functions are unknown (Gill et Glutamate receptors are expressed mainly in the cen- al., 1998). Thus, the potential therapeutic realm of drugs tral nervous system, but several potentially important targeted to glutamate receptors is expanding to include exceptions are worth mentioning. The realization that cells (neural and nonneural) in the periphery. Most re- pancreatic islet cells express glutamate receptors that cently, evidence for a role for ionotropic glutamate re- modulate insulin secretion (Inagaki et al., 1995; Weaver ceptors expressed by plant cells in light signal transduc- et al., 1996, 1998) and that antagonists of NMDA recep- tion has been reported (Lam et al., 1998), suggesting tors expressed by osteoclasts and osteoblasts slow bone that mammalian receptors may have evolved from a more primitive signaling mechanism. 2 Abbreviations: NMDA, N-methyl-D-aspartate; PKA, protein kinase The cloning of the glutamate receptors in the early a A; PKC, protein kinase C; AMPA, -amino-3-hydroxy-5-methyl-4-isox- 1990s has taken the study of glutamate receptor phar- azolepropionic acid; UTR, untranslated region; KBP, kainate-binding protein; RT-PCR, reverse transcription-polymerase chain reaction; macology, physiology, and pathophysiology to the molec- GABA, g-aminobutyric acid; CNS, central nervous system; NO, nitric ular level. Several major reviews of the initial fruits of oxide; ABP, AMPA receptor-binding