A Guide to Glutamate Receptors
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S Efficacy in Treating Bipolar Depression: a Longitudinal Proton Magnetic Resonance Spectroscopy Study
Neuropsychopharmacology (2009) 34, 1810–1818 & 2009 Nature Publishing Group All rights reserved 0893-133X/09 $32.00 www.neuropsychopharmacology.org Decreased Glutamate/Glutamine Levels May Mediate Cytidine’s Efficacy in Treating Bipolar Depression: A Longitudinal Proton Magnetic Resonance Spectroscopy Study Sujung J Yoon*,1, In Kyoon Lyoo2,3, Charlotte Haws4,5, Tae-Suk Kim1, Bruce M Cohen2,6 and 4,5 Perry F Renshaw 1Department of Psychiatry, Catholic University College of Medicine, Seoul, South Korea; 2Department of Psychiatry, Harvard Medical School, Boston, MA, USA; 3Brain Imaging Center and Clinical Research Center, Seoul National University Hospital, Seoul, South Korea; 4Department of 5 Psychiatry, The Brain Institute, University of Utah, Salt Lake City, UT, USA; Department of Veterans Affairs VISN 19 MIRECC, Salt Lake City, UT, 6 USA; Molecular Pharmacology Laboratory, Harvard Medical School, McLean Hospital, Belmont, MA, USA Targeting the glutamatergic system has been suggested as a promising new option for developing treatment strategies for bipolar depression. Cytidine, a pyrimidine, may exert therapeutic effects through a pathway that leads to altered neuronal-glial glutamate cycling. Pyrimidines are also known to exert beneficial effects on cerebral phospholipid metabolism, catecholamine synthesis, and mitochondrial function, which have each been linked to the pathophysiology of bipolar depression. This study was aimed at determining cytidine’s efficacy in bipolar depression and at assessing the longitudinal effects of cytidine on cerebral glutamate/glutamine levels. Thirty-five patients with bipolar depression were randomly assigned to receive the mood-stabilizing drug valproate plus either cytidine or placebo for 12 weeks. Midfrontal cerebral glutamate/glutamine levels were measured using proton magnetic resonance spectroscopy before and after 2, 4, and 12 weeks of oral cytidine administration. -
Glycine Activated Ion Channel Subunits Encoded by Ctenophore
Glycine activated ion channel subunits encoded by PNAS PLUS ctenophore glutamate receptor genes Robert Albersteina, Richard Greya, Austin Zimmeta, David K. Simmonsb, and Mark L. Mayera,1 aLaboratory of Cellular and Molecular Neurophysiology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892; and bThe Whitney Laboratory for Marine Bioscience, University of Florida, St. Augustine, FL 32080 Edited by Christopher Miller, Howard Hughes Medical Institute, Brandeis University, Waltham, MA, and approved September 2, 2015 (received for review July 13, 2015) Recent genome projects for ctenophores have revealed the subunits and glutamate to GluN2 subunits for activation of ion presence of numerous ionotropic glutamate receptors (iGluRs) in channel gating (12, 14–17), as well as depolarization to relieve + Mnemiopsis leidyi and Pleurobrachia bachei, among our earliest ion channel block by extracellular Mg2 (18, 19). The initial metazoan ancestors. Sequence alignments and phylogenetic analy- annotation of the M. leidyi genome identified 16 candidate iGluR sis show that these form a distinct clade from the well-characterized genes (4), whereas in the draft genome of P. bachei, 14 iGluRs AMPA, kainate, and NMDA iGluR subtypes found in vertebrates. were annotated as kainate-like receptors (5). In view of growing Although annotated as glutamate and kainate receptors, crystal interest in the molecular evolution of ion channels and receptors, structures of the ML032222a and PbiGluR3 ligand-binding domains and the pivotal role that ctenophores play in our current un- (LBDs) reveal endogenous glycine in the binding pocket, whereas derstanding of nervous system development (20), we initiated a ligand-binding assays show that glycine binds with nanomolar af- structural and functional characterization of glutamate receptors finity; biochemical assays and structural analysis establish that glu- expressed in both species. -
The G Protein-Coupled Glutamate Receptors As Novel Molecular Targets in Schizophrenia Treatment— a Narrative Review
Journal of Clinical Medicine Review The G Protein-Coupled Glutamate Receptors as Novel Molecular Targets in Schizophrenia Treatment— A Narrative Review Waldemar Kryszkowski 1 and Tomasz Boczek 2,* 1 General Psychiatric Ward, Babinski Memorial Hospital in Lodz, 91229 Lodz, Poland; [email protected] 2 Department of Molecular Neurochemistry, Medical University of Lodz, 92215 Lodz, Poland * Correspondence: [email protected] Abstract: Schizophrenia is a severe neuropsychiatric disease with an unknown etiology. The research into the neurobiology of this disease led to several models aimed at explaining the link between perturbations in brain function and the manifestation of psychotic symptoms. The glutamatergic hypothesis postulates that disrupted glutamate neurotransmission may mediate cognitive and psychosocial impairments by affecting the connections between the cortex and the thalamus. In this regard, the greatest attention has been given to ionotropic NMDA receptor hypofunction. However, converging data indicates metabotropic glutamate receptors as crucial for cognitive and psychomotor function. The distribution of these receptors in the brain regions related to schizophrenia and their regulatory role in glutamate release make them promising molecular targets for novel antipsychotics. This article reviews the progress in the research on the role of metabotropic glutamate receptors in schizophrenia etiopathology. Citation: Kryszkowski, W.; Boczek, T. The G Protein-Coupled Glutamate Keywords: schizophrenia; metabotropic glutamate receptors; positive allosteric modulators; negative Receptors as Novel Molecular Targets allosteric modulators; drug development; animal models of schizophrenia; clinical trials in Schizophrenia Treatment—A Narrative Review. J. Clin. Med. 2021, 10, 1475. https://doi.org/10.3390/ jcm10071475 1. Introduction Academic Editors: Andreas Reif, Schizophrenia is a common debilitating disease affecting about 0.3–1% of the human Blazej Misiak and Jerzy Samochowiec population worldwide [1]. -
Kainate Receptors in Health and Disease
View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Neuron Review Kainate Receptors in Health and Disease Juan Lerma1,* and Joana M. Marques1 1Instituto de Neurociencias, CSIC-UMH, San Juan de Alicante, 03550 Spain *Correspondence: [email protected] http://dx.doi.org/10.1016/j.neuron.2013.09.045 Our understanding of the molecular properties of kainate receptors and their involvement in synaptic phys- iology has progressed significantly over the last 30 years. A plethora of studies indicate that kainate receptors are important mediators of the pre- and postsynaptic actions of glutamate, although the mechanisms under- lying such effects are still often a topic for discussion. Three clear fields related to their behavior have emerged: there are a number of interacting proteins that pace the properties of kainate receptors; their activity is unconventional since they can also signal through G proteins, behaving like metabotropic recep- tors; they seem to be linked to some devastating brain diseases. Despite the significant progress in their importance in brain function, kainate receptors remain somewhat puzzling. Here we examine discoveries linking these receptors to physiology and their probable implications in disease, in particular mood disorders, and propose some ideas to obtain a deeper understanding of these intriguing proteins. A Historical Overview The absence of specific antibodies against different KAR Most excitatory synapses in the brain use the amino acid gluta- subunits has been a significant limitation in terms of exploring re- mate as a neurotransmitter. Since the excitatory properties of ceptor distribution. Thus, most of the information regarding their glutamate were postulated nearly 40 years ago, an extraordinary tissue expression comes from in situ hybridization studies that, wealth of data has accumulated on the types of synaptic re- although informative, cannot reveal the subcellular distribution sponses triggered by this neurotransmitter. -
Lysophosphatidic Acid Signaling in the Nervous System
Neuron Review Lysophosphatidic Acid Signaling in the Nervous System Yun C. Yung,1,3 Nicole C. Stoddard,1,2,3 Hope Mirendil,1 and Jerold Chun1,* 1Molecular and Cellular Neuroscience Department, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA 92037, USA 2Biomedical Sciences Graduate Program, University of California, San Diego School of Medicine, La Jolla, CA 92037, USA 3Co-first author *Correspondence: [email protected] http://dx.doi.org/10.1016/j.neuron.2015.01.009 The brain is composed of many lipids with varied forms that serve not only as structural components but also as essential signaling molecules. Lysophosphatidic acid (LPA) is an important bioactive lipid species that is part of the lysophospholipid (LP) family. LPA is primarily derived from membrane phospholipids and signals through six cognate G protein-coupled receptors (GPCRs), LPA1-6. These receptors are expressed on most cell types within central and peripheral nervous tissues and have been functionally linked to many neural pro- cesses and pathways. This Review covers a current understanding of LPA signaling in the nervous system, with particular focus on the relevance of LPA to both physiological and diseased states. Introduction LPA synthesis/degradative enzymes (reviewed in Sigal et al., The human brain is composed of approximately 60%–70% lipids 2005; Brindley and Pilquil, 2009; Perrakis and Moolenaar, by dry weight (Svennerholm et al., 1994). These lipids can be 2014). In view of the broad neurobiological influences of LPA divided into two major pools, structural and signaling, which signaling, its dysregulation may lead to diverse neuropathologies include well-known families such as cholesterol, fatty acids, ei- (Bandoh et al., 2000; Houben and Moolenaar, 2011; Yung et al., cosanoids, endocannabinoids, and prostaglandins (Figure 1). -
Interplay Between Gating and Block of Ligand-Gated Ion Channels
brain sciences Review Interplay between Gating and Block of Ligand-Gated Ion Channels Matthew B. Phillips 1,2, Aparna Nigam 1 and Jon W. Johnson 1,2,* 1 Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA 15260, USA; [email protected] (M.B.P.); [email protected] (A.N.) 2 Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA 15260, USA * Correspondence: [email protected]; Tel.: +1-(412)-624-4295 Received: 27 October 2020; Accepted: 26 November 2020; Published: 1 December 2020 Abstract: Drugs that inhibit ion channel function by binding in the channel and preventing current flow, known as channel blockers, can be used as powerful tools for analysis of channel properties. Channel blockers are used to probe both the sophisticated structure and basic biophysical properties of ion channels. Gating, the mechanism that controls the opening and closing of ion channels, can be profoundly influenced by channel blocking drugs. Channel block and gating are reciprocally connected; gating controls access of channel blockers to their binding sites, and channel-blocking drugs can have profound and diverse effects on the rates of gating transitions and on the stability of channel open and closed states. This review synthesizes knowledge of the inherent intertwining of block and gating of excitatory ligand-gated ion channels, with a focus on the utility of channel blockers as analytic probes of ionotropic glutamate receptor channel function. Keywords: ligand-gated ion channel; channel block; channel gating; nicotinic acetylcholine receptor; ionotropic glutamate receptor; AMPA receptor; kainate receptor; NMDA receptor 1. Introduction Neuronal information processing depends on the distribution and properties of the ion channels found in neuronal membranes. -
(NMDA) Receptor Encephalitis Is an Autoimmune Seizures and Autonomic Dysfunction
Nonprofit Organization U.S. Postage PAID Twin Cities, MN VOLUME 23, NUMBER 4 200 University Ave. E. Permit No. 5388 St. Paul, MN 55101 651-291-2848 ADDRESSwww.gillettechildrens.org SERVICE REQUESTED VOLUME 23, NUMBER 4 2014 A Pediatric Perspective focuses on specialized topics in pediatrics, orthopedics, neurology, neurosurgery and rehabilitation medicine. Diagnosing and Treating Anti- KEY INSIGHTS To subscribe to or unsubscribe from A Pediatric Perspective, please send an email to [email protected]. N-Methyl-D-Aspartate (NMDA) ■ Anti-NMDA receptor encephalitis Editor-in-Chief – Steven Koop, M.D. is a relatively common and treatable Editor – Ellen Shriner Receptor Encephalitis cause of encephalitis in pediatric Designers – Becky Wright, Kim Goodness patients. Photographers – Anna Bittner, Amanda Moen, M.D., pediatric neurologist Paul DeMarchi ■ Common symptoms include person- Copyright 2014. Gillette Children’s Specialty ality change, abnormal movements, Amanda Moen, M.D. Healthcare. All rights reserved. Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis is an autoimmune seizures and autonomic dysfunction. condition in which the body produces antibodies that act against receptors in ■ If these symptoms are present, an the brain, resulting in both neurologic and psychiatric symptoms. Common urgent child neurology evaluation is symptoms include personality change, psychosis, abnormal movements, indicated and an evaluation for anti- To make a referral, call 651-325-2200 or seizures and autonomic dysfunction. The antibodies associated with this NMDA receptor encephalitis should Pediatric neurologist Amanda Moen, M.D., treats children 855-325-2200 (toll-free). condition were first identified in 2005, and since then it has become recognized be initiated. who have epilepsy and other neurological conditions. -
From NMDA Receptor Hypofunction to the Dopamine Hypothesis of Schizophrenia J
REVIEW The Neuropsychopharmacology of Phencyclidine: From NMDA Receptor Hypofunction to the Dopamine Hypothesis of Schizophrenia J. David Jentsch, Ph.D., and Robert H. Roth, Ph.D. Administration of noncompetitive NMDA/glutamate effects of these drugs are discussed, especially with regard to receptor antagonists, such as phencyclidine (PCP) and differing profiles following single-dose and long-term ketamine, to humans induces a broad range of exposure. The neurochemical effects of NMDA receptor schizophrenic-like symptomatology, findings that have antagonist administration are argued to support a contributed to a hypoglutamatergic hypothesis of neurobiological hypothesis of schizophrenia, which includes schizophrenia. Moreover, a history of experimental pathophysiology within several neurotransmitter systems, investigations of the effects of these drugs in animals manifested in behavioral pathology. Future directions for suggests that NMDA receptor antagonists may model some the application of NMDA receptor antagonist models of behavioral symptoms of schizophrenia in nonhuman schizophrenia to preclinical and pathophysiological research subjects. In this review, the usefulness of PCP are offered. [Neuropsychopharmacology 20:201–225, administration as a potential animal model of schizophrenia 1999] © 1999 American College of is considered. To support the contention that NMDA Neuropsychopharmacology. Published by Elsevier receptor antagonist administration represents a viable Science Inc. model of schizophrenia, the behavioral and neurobiological KEY WORDS: Ketamine; Phencyclidine; Psychotomimetic; widely from the administration of purportedly psychot- Memory; Catecholamine; Schizophrenia; Prefrontal cortex; omimetic drugs (Snyder 1988; Javitt and Zukin 1991; Cognition; Dopamine; Glutamate Jentsch et al. 1998a), to perinatal insults (Lipska et al. Biological psychiatric research has seen the develop- 1993; El-Khodor and Boksa 1997; Moore and Grace ment of many putative animal models of schizophrenia. -
Cellular Trafficking of Nicotinic Acetylcholine Receptors
npg Acta Pharmacol Sin 2009 Jun; 30 (6): 656–662 Review Cellular trafficking of nicotinic acetylcholine receptors Paul A ST JOHN* Department of Cell Biology and Anatomy, University of Arizona College of Medicine, Tucson, AZ 85724, USA Nicotinic acetylcholine receptors (nAChRs) play critical roles throughout the body. Precise regulation of the cellular loca- tion and availability of nAChRs on neurons and target cells is critical to their proper function. Dynamic, post-translational regulation of nAChRs, particularly control of their movements among the different compartments of cells, is an important aspect of that regulation. A combination of new information and new techniques has the study of nAChR trafficking poised for new breakthroughs. Keywords: membrane traffic; protein traffic; biosynthesis; endocytosis; endoplasmic reticulum-associated degradation Acta Pharmacologica Sinica (2009) 30: 656–662; doi: 10.1038/aps.2009.76 Introduction ways, but two particular perturbations have been especially well studied and exert their effects at least in part by altering Nicotinic acetylcholine receptors (nAChRs) mediate the trafficking of nAChRs: 1) denervation changes the total synaptic transmission in the CNS, in autonomic ganglia, and number, the distribution, and the turnover rate of nAChRs in at neuromuscular junctions and other peripheral synapses. skeletal muscle; 2) prolonged exposure to nicotine increases The functional properties of these synapses differ, but in each the total number of nAChRs in neurons. Several of the stud- case, properly functional signaling requires cellular control ies reviewed here addressed the mechanisms by which these of the number, type, and location of nAChRs. Trafficking treatments alter nAChR trafficking. Other authors in this of nAChRs – the movement of nAChRs between compart- special issue will address other aspects of the effects of nico- ments of a cell, including the cell's biosynthetic and degrada- tine on nAChRs. -
Sex Differences in Glutamate Receptor Gene Expression in Major Depression and Suicide
Molecular Psychiatry (2015) 20, 1057–1068 © 2015 Macmillan Publishers Limited All rights reserved 1359-4184/15 www.nature.com/mp IMMEDIATE COMMUNICATION Sex differences in glutamate receptor gene expression in major depression and suicide AL Gray1, TM Hyde2,3, A Deep-Soboslay2, JE Kleinman2 and MS Sodhi1,4 Accumulating data indicate that the glutamate system is disrupted in major depressive disorder (MDD), and recent clinical research suggests that ketamine, an antagonist of the N-methyl-D-aspartate (NMDA) glutamate receptor (GluR), has rapid antidepressant efficacy. Here we report findings from gene expression studies of a large cohort of postmortem subjects, including subjects with MDD and controls. Our data reveal higher expression levels of the majority of glutamatergic genes tested in the dorsolateral prefrontal cortex (DLPFC) in MDD (F21,59 = 2.32, P = 0.006). Posthoc data indicate that these gene expression differences occurred mostly in the female subjects. Higher expression levels of GRIN1, GRIN2A-D, GRIA2-4, GRIK1-2, GRM1, GRM4, GRM5 and GRM7 were detected in the female patients with MDD. In contrast, GRM5 expression was lower in male MDD patients relative to male controls. When MDD suicides were compared with MDD non-suicides, GRIN2B, GRIK3 and GRM2 were expressed at higher levels in the suicides. Higher expression levels were detected for several additional genes, but these were not statistically significant after correction for multiple comparisons. In summary, our analyses indicate a generalized disruption of the regulation of the GluRs in the DLPFC of females with MDD, with more specific GluR alterations in the suicides and in the male groups. -
Chapter Chapter 2
Chapter Chapter 2 Attenuated AMPA receptor expression allows glioblastoma cell survival in glutamate-rich environment Dannis G. van Vuurden, Maryam Yazdani, Ingeborg Bosma, Richard A.J.F. Broekhuizen, Tjeerd J. Postma, Jan J. Heimans, Paul van der Valk, Eleonora Aronica, Bakhos A. Tannous, Thomas Würdinger, Gertjan J. L. Kaspers, Jacqueline Cloos PLoS ONE 2009; 4(6): e5953 23 Proefschrift1.indd 23 24-04-14 13:54 ABSTRACT Background: Glioblastoma multiforme (GBM) cells secrete large amounts of glutamate that can trigger AMPA-type glutamate receptors (AMPARs). This commonly results in Na+ and Ca2+-permeability and thereby in excitotoxic cell death of the surrounding neurons. Here we investigated how the GBM cells themselves survive in a glutamate-rich environment. Methods and Findings: In silico analysis of published reports shows down-regulation of all ionotropic glutamate receptors in GBM as compared to normal brain. In vitro, in all GBM samples tested, mRNA expression of AMPAR subunit GluR1, 2 and 4 was relatively low compared to adult and fetal total brain mRNA and adult cerebellum mRNA. These findings were in line with primary GBM samples, in which protein expression patterns were down- regulated as compared to the normal tissue. Furthermore, mislocalized expression of these receptors was found. Sequence analysis of GluR2 RNA in primary and established GBM cell lines showed that the GluR2 subunit was found to be partly unedited. Conclusions: Together with the lack of functional effect of AMPAR inhibition by NBQX our results suggest that down-regulation and non-functionality of AMPARs, enable GBM cells to survive in a high glutamate environment without going into excitotoxic cell death themselves. -
The Interplay Between Neurons and Glia in Synapse Development And
Available online at www.sciencedirect.com ScienceDirect The interplay between neurons and glia in synapse development and plasticity Jeff A Stogsdill and Cagla Eroglu In the brain, the formation of complex neuronal networks and regulate distinct aspects of synaptic development and amenable to experience-dependent remodeling is complicated circuit connectivity. by the diversity of neurons and synapse types. The establishment of a functional brain depends not only on The intricate communication between neurons and glia neurons, but also non-neuronal glial cells. Glia are in and their cooperative roles in synapse formation are now continuous bi-directional communication with neurons to direct coming to light due in large part to advances in genetic the formation and refinement of synaptic connectivity. This and imaging tools. This article will examine the progress article reviews important findings, which uncovered cellular made in our understanding of the role of mammalian and molecular aspects of the neuron–glia cross-talk that perisynaptic glia (astrocytes and microglia) in synapse govern the formation and remodeling of synapses and circuits. development, maturation, and plasticity since the previ- In vivo evidence demonstrating the critical interplay between ous Current Opinion article [1]. An integration of past and neurons and glia will be the major focus. Additional attention new findings of glial control of synapse development and will be given to how aberrant communication between neurons plasticity is tabulated in Box 1. and glia may contribute to neural pathologies. Address Glia control the formation of synaptic circuits Department of Cell Biology, Duke University Medical Center, Durham, In the CNS, glial cells are in tight association with NC 27710, USA synapses in all brain regions [2].