Abstract
Many physiologic effects of L-glutamate, the major excitatory neurotransmitter in the mamma-lian 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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1469-1658 |
| Number of pages | 190 |
| Journal | Pharmacological Reviews |
| Volume | 73 |
| Issue number | 4 |
| DOIs | |
| State | Published - Oct 2021 |
Funding
K.B.H. was supported by National Institutes of Health National Institute of Neurological Disorders and Stroke [Grants NS097536 and NS116055] and National Institute of General Medical Sciences [Grant GM103546]; L.P.W. was supported by National Institutes of Health National Institute of Neurological Disorders and Stroke [Grant NS088479]; A.I.S was supported by National Institutes of Health National Institute of Neurological Disorders and Stroke [Grants NS083660 and NS107253] and National Cancer Institute [Grant CA206573] and the National Science Foundation [1818086]; I.H.G. was supported by UK Research and Innovation [MC_U105174197] and the Biotechnology and Biological Sciences Research Council [BB/N002113/1]; H.F. was supported by the National Institutes of Health National Institutes of Health National Institute of Neurological Disorders and Stroke [Grants NS111745 and NS113632] and National Institute of Mental Health [Grant MH085926], Robertson funds at Cold Spring Harbor Laboratory, Doug Fox Alzheimer's Fund, Austin's Purpose, Heartfelt Wing Alzheimer's Fund, and the Gertrude and Louis Feil Family Trust; C-M.L. was supported by the National University of Singapore [R184000261101]; T.N. was supported by National Institutes of Health National Institute of Mental Health [Grant MH123474]; C.J.M. was supported by the Intramural Research Program of the National Institutes of Health Eunice Kennedy Shriver National Institute of Child Health and Human Development; J.S.D. was supported by the Intramural Research Program of the National Institutes of Health National Institute of Neurologic Disorders and Stroke; D.B. was supported by operating grants from the Canadian Institutes of Health Research [FRN 136832, FRN 142431, FRN 162317]; M.L.D. was supported by the National Institutes of Health National Institute of Neurological Disorders and Stroke [Grant NS040701]; G.T.S. was supported by National Institutes of Health National Institute of Neurological Disorders and Stroke [Grant NS105502]; V.J. was supported by National Institutes of Health National Institute of General Medical Sciences [Grant GM122528]; S.A.S. was supported by the National Institutes of Health National Institute of Neurological Disorders and Stroke [Grant NS105804]; H.Y. was supported by National Institutes of Health Eunice Kennedy Shriver National Institute of Child Health and Human Development [Grant HD082373]; C.C. was supported by National Institutes of Health National Institute of Neurological Disorders and Stroke [Grant NS113530]; and S.F.T. was supported by the National Institutes of Health National Institute of Neurological Disorders and Stroke [Grant NS111619]. K.B.H is principal investigator on a research grant from Janssen Research and Development to the University of Montana. F.S.M is co-inventor on Pfizer- and Novartis-owned Intellectual Property that includes allosteric NMDA receptor modulators; is Chief Scientific Officer of MindImmune Therapeutics, Inc.; and is a consultant to Gilgamesh Therapeutics, Inc. H.F. was a principal investigator on a research grant from Allergan. H.Y. is principal investigator on a research grant from Sage Therapeutics to Emory University School of Medicine. S.F.T. is principal investigator on research grants from Biogen and Janssen to Emory; is a member of the Scientific Advisory Board for Eumentis Inc, Sage Therapeutics, the GRIN2B Foundation, the CureGRIN Foundation; is cofounder of NeurOp Inc and Agrithera Inc.; has received licensing fees and royalties from Emory; and is co-inventor on Emory-owned Intellectual Property that includes allosteric modulators of NMDA receptor function. All other authors have no conflicts of interest to declare. Address correspondence to: Stephen F. Traynelis, Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Rollins Research Center, 1510 Clifton Rd., Atlanta, GA 30322-3090. E-mail: [email protected] K.B.H. was supported by National Institutes of Health National Institute of Neurological Disorders and Stroke [Grants NS097536 and NS116055] and National Institute of General Medical Sciences [Grant GM103546]; L.P.W. was supported by National Institutes of Health National Institute of Neurological Disorders and Stroke [Grant NS088479]; A.I.S was supported by National Institutes of Health National Institute of Neurological Disorders and Stroke [Grants NS083660 and NS107253] and National Cancer Institute [Grant CA206573] and the National Science Foundation [1818086]; I.H.G. was supported by UK Research and Innovation [MC_U105174197] and the Biotechnology and Biological Sciences Research Council [BB/N002113/1]; H.F. was supported by the National Institutes of Health National Institutes of Health National Institute of Neurological Disorders and Stroke [Grants NS111745 and NS113632] and National Institute of Mental Health [Grant MH085926], Robertson funds at Cold Spring Harbor Laboratory, Doug Fox Alzheimer’s Fund, Austin’s Purpose, Heartfelt Wing Alzheimer’s Fund, and the Gertrude and Louis Feil Family Trust; C-M.L. was supported by the National University of Singapore [R184000261101]; T.N. was supported by National Institutes of Health National Institute of Mental Health [Grant MH123474]; C.J.M. was supported by the Intramural Research Program of the National Institutes of Health Eunice Kennedy Shriver National Institute of Child Health and Human Development; J.S.D. was supported by the Intramural Research Program of the National Institutes of Health National Institute of Neurologic Disorders and Stroke; D.B. was supported by operating grants from the Canadian Institutes of Health Research [FRN 136832, FRN 142431, FRN 162317]; M.L.D. was supported by the National Institutes of Health National Institute of Neurological Disorders and Stroke [Grant NS040701]; G.T.S. was supported by National Institutes of Health National Institute of Neurological Disorders and Stroke [Grant NS105502]; V.J. was supported by National Institutes of Health National Institute of General Medical Sciences [Grant GM122528]; S.A.S. was supported by the National Institutes of Health National Institute of Neurological Disorders and Stroke [Grant NS105804]; H.Y. was supported by National Institutes of Health Eunice Kennedy Shriver National Institute of Child Health and Human Development [Grant HD082373]; C.C. was supported by National Institutes of Health National Institute of Neurological Disorders and Stroke [Grant NS113530]; and S.F.T. was supported by the National Institutes of Health National Institute of Neurological Disorders and Stroke [Grant NS111619].
ASJC Scopus subject areas
- Molecular Medicine
- Pharmacology