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Neuropharmacology Jul 2018gamma-Aminobutyric acid (GABA)-mediated inhibitory neurotransmission and the gene products involved were discovered during the mid-twentieth century. Historically,... (Review)
Review
gamma-Aminobutyric acid (GABA)-mediated inhibitory neurotransmission and the gene products involved were discovered during the mid-twentieth century. Historically, myriad existing nervous system drugs act as positive and negative allosteric modulators of these proteins, making GABA a major component of modern neuropharmacology, and suggesting that many potential drugs will be found that share these targets. Although some of these drugs act on proteins involved in synthesis, degradation, and membrane transport of GABA, the GABA receptors Type A (GABAR) and Type B (GABAR) are the targets of the great majority of GABAergic drugs. This discovery is due in no small part to Professor Norman Bowery. Whereas the topic of GABAR is appropriately emphasized in this special issue, Norman Bowery also made many insights into GABAR pharmacology, the topic of this article. GABAR are members of the ligand-gated ion channel receptor superfamily, a chloride channel family of a dozen or more heteropentameric subtypes containing 19 possible different subunits. These subtypes show different brain regional and subcellular localization, age-dependent expression, and potential for plastic changes with experience including drug exposure. Not only are GABAR the targets of agonist depressants and antagonist convulsants, but most GABAR drugs act at other (allosteric) binding sites on the GABAR proteins. Some anxiolytic and sedative drugs, like benzodiazepine and related drugs, act on GABAR subtype-dependent extracellular domain sites. General anesthetics including alcohols and neurosteroids act at GABAR subunit-interface trans-membrane sites. Ethanol at high anesthetic doses acts on GABAR subtype-dependent trans-membrane domain sites. Ethanol at low intoxicating doses acts at GABAR subtype-dependent extracellular domain sites. Thus GABAR subtypes possess pharmacologically specific receptor binding sites for a large group of different chemical classes of clinically important neuropharmacological agents. This article is part of the "Special Issue Dedicated to Norman G. Bowery".
Topics: Allosteric Regulation; Animals; GABA-A Receptor Agonists; GABA-A Receptor Antagonists; Humans; Receptors, GABA-A
PubMed: 29407219
DOI: 10.1016/j.neuropharm.2018.01.036 -
Molecules (Basel, Switzerland) Jul 2020The γ-aminobutyric acid (GABA) type B receptor (GABA-R) belongs to class C of the G-protein coupled receptors (GPCRs). Together with the GABA receptor, the receptor... (Review)
Review
The γ-aminobutyric acid (GABA) type B receptor (GABA-R) belongs to class C of the G-protein coupled receptors (GPCRs). Together with the GABA receptor, the receptor mediates the neurotransmission of GABA, the main inhibitory neurotransmitter in the central nervous system (CNS). In recent decades, the receptor has been extensively studied with the intention being to understand pathophysiological roles, structural mechanisms and develop drugs. The dysfunction of the receptor is linked to a broad variety of disorders, including anxiety, depression, alcohol addiction, memory and cancer. Despite extensive efforts, few compounds are known to target the receptor, and only the agonist baclofen is approved for clinical use. The receptor is a mandatory heterodimer of the GABA and GABA subunits, and each subunit is composed of an extracellular Venus Flytrap domain (VFT) and a transmembrane domain of seven α-helices (7TM domain). In this review, we briefly present the existing knowledge about the receptor structure, activation and compounds targeting the receptor, emphasizing the role of the receptor in previous and future drug design and discovery efforts.
Topics: Baclofen; Binding Sites; Drug Development; GABA-B Receptor Antagonists; Humans; Ligands; Models, Molecular; Protein Conformation, alpha-Helical; Receptors, GABA-B
PubMed: 32646032
DOI: 10.3390/molecules25133093 -
Trends in Biochemical Sciences Jun 2021GABA receptors are pentameric ligand-gated ion channels that mediate most fast neuronal inhibition in the brain. In addition to their important physiological roles, they... (Review)
Review
GABA receptors are pentameric ligand-gated ion channels that mediate most fast neuronal inhibition in the brain. In addition to their important physiological roles, they are noteworthy in their rich pharmacology; prominent drugs used for anxiety, insomnia, and general anesthesia act through positive modulation of GABA receptors. Direct structural information for how these drugs work was absent until recently. Efforts in structural biology over the past few years have revealed how important drug classes and natural products interact with the GABA receptor, providing a foundation for studies in dynamics and structure-guided drug design. Here, we review recent developments in GABA receptor structural pharmacology, focusing on subunit assemblies of the receptor found at synapses.
Topics: Ligand-Gated Ion Channels; Receptors, GABA-A
PubMed: 33674151
DOI: 10.1016/j.tibs.2021.01.011 -
Seizure Oct 2022Epilepsy is a paroxysmal brain disorder that results from an imbalance between neuronal excitation and inhibition. Gamma-aminobutyric acid (GABA) is the most important... (Review)
Review
Epilepsy is a paroxysmal brain disorder that results from an imbalance between neuronal excitation and inhibition. Gamma-aminobutyric acid (GABA) is the most important inhibitory neurotransmitter in the brain and plays an important role in the occurrence and development of epilepsy. Abnormalities in all aspects of GABA metabolism, including GABA synthesis, transport, genes encoding GABA receptors, and GABA inactivation, may lead to epilepsy. GABRA1, GABRA2, GABRA5, GABRB1, GABRB2, GABRB3, GABRG2 and GABBR2 are genes that encode GABA receptors and are commonly associated with epilepsy. Mutations of these genes lead to a variety of epilepsy syndromes with different clinical phenotypes, primarily by down regulating receptor expression and reducing the amplitude of GABA-evoked potentials. GABA is metabolized by GABA transaminase and succinate semi aldehyde dehydrogenase, which are encoded by the ABAT and ALDH5A1 genes, respectively. Mutations of these genes result in symptoms related to deficiency of GABA transaminase and succinate semi aldehyde dehydrogenase, such as epilepsy and cognitive impairment. Most of the variation in genes associated with GABA metabolism are accompanied by developmental disorders. This review focuses on advances in understanding the relationship between genetic variation in GABA metabolism and epilepsy to establish a basis for the accurate diagnosis and treatment of epilepsy.
Topics: 4-Aminobutyrate Transaminase; Aldehyde Dehydrogenase; Epilepsy; Humans; Mutation; Receptors, GABA; Receptors, GABA-A; Succinates; gamma-Aminobutyric Acid
PubMed: 35850019
DOI: 10.1016/j.seizure.2022.07.007 -
Experimental & Molecular Medicine Apr 2018Inhibitory neurotransmission plays a key role in anxiety disorders, as evidenced by the anxiolytic effect of the benzodiazepine class of γ-aminobutyric acid (GABA)... (Review)
Review
Inhibitory neurotransmission plays a key role in anxiety disorders, as evidenced by the anxiolytic effect of the benzodiazepine class of γ-aminobutyric acid (GABA) receptor agonists and the recent discovery of anxiety-associated variants in the molecular components of inhibitory synapses. Accordingly, substantial interest has focused on understanding how inhibitory neurons and synapses contribute to the circuitry underlying adaptive and pathological anxiety behaviors. A key element of the anxiety circuitry is the amygdala, which integrates information from cortical and thalamic sensory inputs to generate fear and anxiety-related behavioral outputs. Information processing within the amygdala is heavily dependent on inhibitory control, although the specific mechanisms by which amygdala GABAergic neurons and synapses regulate anxiety-related behaviors are only beginning to be uncovered. Here, we summarize the current state of knowledge and highlight open questions regarding the role of inhibition in the amygdala anxiety circuitry. We discuss the inhibitory neuron subtypes that contribute to the processing of anxiety information in the basolateral and central amygdala, as well as the molecular determinants, such as GABA receptors and synapse organizer proteins, that shape inhibitory synaptic transmission within the anxiety circuitry. Finally, we conclude with an overview of current and future approaches for converting this knowledge into successful treatment strategies for anxiety disorders.
Topics: Amygdala; Animals; Anxiety; Biomarkers; Disease Models, Animal; GABAergic Neurons; Humans; Molecular Targeted Therapy; Neurons; Receptors, GABA; Signal Transduction; Synapses; Synaptic Transmission; gamma-Aminobutyric Acid
PubMed: 29628509
DOI: 10.1038/s12276-018-0063-8 -
Handbook of Experimental Pharmacology 2019Current GABAergic sleep-promoting medications were developed pragmatically, without making use of the immense diversity of GABA receptors. Pharmacogenetic experiments...
Current GABAergic sleep-promoting medications were developed pragmatically, without making use of the immense diversity of GABA receptors. Pharmacogenetic experiments are leading to an understanding of the circuit mechanisms in the hypothalamus by which zolpidem and similar compounds induce sleep at α2βγ2-type GABA receptors. Drugs acting at more selective receptor types, for example, at receptors containing the α2 and/or α3 subunits expressed in hypothalamic and brain stem areas, could in principle be useful as hypnotics/anxiolytics. A highly promising sleep-promoting drug, gaboxadol, which activates αβδ-type receptors failed in clinical trials. Thus, for the time being, drugs such as zolpidem, which work as positive allosteric modulators at GABA receptors, continue to be some of the most effective compounds to treat primary insomnia.
Topics: Hypnotics and Sedatives; Receptors, GABA; Receptors, GABA-A; Sleep; Zolpidem
PubMed: 28993837
DOI: 10.1007/164_2017_56 -
Nature Apr 2022Type A γ-aminobutyric acid receptors (GABARs) are pentameric ligand-gated chloride channels that mediate fast inhibitory signalling in neural circuits and can be...
Type A γ-aminobutyric acid receptors (GABARs) are pentameric ligand-gated chloride channels that mediate fast inhibitory signalling in neural circuits and can be modulated by essential medicines including general anaesthetics and benzodiazepines. Human GABAR subunits are encoded by 19 paralogous genes that can, in theory, give rise to 495,235 receptor types. However, the principles that govern the formation of pentamers, the permutational landscape of receptors that may emerge from a subunit set and the effect that this has on GABAergic signalling remain largely unknown. Here we use cryogenic electron microscopy to determine the structures of extrasynaptic GABARs assembled from α4, β3 and δ subunits, and their counterparts incorporating γ2 instead of δ subunits. In each case, we identified two receptor subtypes with distinct stoichiometries and arrangements, all four differing from those previously observed for synaptic, α1-containing receptors. This, in turn, affects receptor responses to physiological and synthetic modulators by creating or eliminating ligand-binding sites at subunit interfaces. We provide structural and functional evidence that selected GABAR arrangements can act as coincidence detectors, simultaneously responding to two neurotransmitters: GABA and histamine. Using assembly simulations and single-cell RNA sequencing data, we calculated the upper bounds for receptor diversity in recombinant systems and in vivo. We propose that differential assembly is a pervasive mechanism for regulating the physiology and pharmacology of GABARs.
Topics: Benzodiazepines; Binding Sites; Cryoelectron Microscopy; Histamine; Humans; Ligands; Protein Subunits; RNA-Seq; Receptors, GABA-A; Signal Transduction; Single-Cell Analysis; gamma-Aminobutyric Acid
PubMed: 35355020
DOI: 10.1038/s41586-022-04517-3 -
Nature Jul 2018Fast inhibitory neurotransmission in the brain is principally mediated by the neurotransmitter GABA (γ-aminobutyric acid) and its synaptic target, the type A GABA...
Fast inhibitory neurotransmission in the brain is principally mediated by the neurotransmitter GABA (γ-aminobutyric acid) and its synaptic target, the type A GABA receptor (GABA receptor). Dysfunction of this receptor results in neurological disorders and mental illnesses including epilepsy, anxiety and insomnia. The GABA receptor is also a prolific target for therapeutic, illicit and recreational drugs, including benzodiazepines, barbiturates, anaesthetics and ethanol. Here we present high-resolution cryo-electron microscopy structures of the human α1β2γ2 GABA receptor, the predominant isoform in the adult brain, in complex with GABA and the benzodiazepine site antagonist flumazenil, the first-line clinical treatment for benzodiazepine overdose. The receptor architecture reveals unique heteromeric interactions for this important class of inhibitory neurotransmitter receptor. This work provides a template for understanding receptor modulation by GABA and benzodiazepines, and will assist rational approaches to therapeutic targeting of this receptor for neurological disorders and mental illness.
Topics: Benzodiazepines; Bicuculline; Binding, Competitive; Brain Chemistry; Cell Membrane; Cryoelectron Microscopy; Flumazenil; GABA Modulators; Glycosylation; HEK293 Cells; Humans; Immunoglobulin Fab Fragments; Ligands; Models, Molecular; Receptors, GABA-A; gamma-Aminobutyric Acid
PubMed: 29950725
DOI: 10.1038/s41586-018-0255-3 -
Biomolecules Nov 2022Benzodiazepines (BZDs) are a class of widely prescribed psychotropic drugs that target GABA receptors (GABARs) to tune inhibitory synaptic signaling throughout the... (Review)
Review
Benzodiazepines (BZDs) are a class of widely prescribed psychotropic drugs that target GABA receptors (GABARs) to tune inhibitory synaptic signaling throughout the central nervous system. Despite knowing their molecular target for over 40 years, we still do not fully understand the mechanism of modulation at the level of the channel protein. Nonetheless, functional studies, together with recent cryo-EM structures of GABA(α1)(βX)(γ2) receptors in complex with BZDs, provide a wealth of information to aid in addressing this gap in knowledge. Here, mechanistic interpretations of functional and structural evidence for the action of BZDs at GABA(α1)(βX)(γ2) receptors are reviewed. The goal is not to describe each of the many studies that are relevant to this discussion nor to dissect in detail all the effects of individual mutations or perturbations but rather to highlight general mechanistic principles in the context of recent structural information.
Topics: Benzodiazepines; Receptors, GABA-A; gamma-Aminobutyric Acid
PubMed: 36551212
DOI: 10.3390/biom12121784 -
The Lancet. Psychiatry Dec 2020Neuroinflammation is a multifaceted physiological and pathophysiological response of the brain to injury and disease. Given imaging findings of 18 kDa translocator... (Review)
Review
Neuroinflammation is a multifaceted physiological and pathophysiological response of the brain to injury and disease. Given imaging findings of 18 kDa translocator protein (TSPO) and the development of radioligands for other inflammatory targets, PET imaging of neuroinflammation is at a particularly promising stage. This Review critically evaluates PET imaging results of inflammation in psychiatric disorders, including major depressive disorder, schizophrenia and psychosis disorders, substance use, and obsessive-compulsive disorder. We also consider promising new targets that can be measured in the brain, such as monoamine oxidase B, cyclooxygenase-1 and cyclooxygenase-2, colony stimulating factor 1 receptor, and the purinergic P2X7 receptor. Thus far, the most compelling TSPO imaging results have arguably been found in major depressive disorder, for which consistent increases have been observed, and in schizophrenia and psychosis, for which patients show reduced TSPO levels. This pattern highlights the importance of validating brain biomarkers of neuroinflammation for each condition separately before moving on to patient stratification and treatment monitoring trials.
Topics: Animals; Biomarkers; Brain; Humans; Inflammation; Mental Disorders; Positron-Emission Tomography; Receptors, GABA
PubMed: 33098761
DOI: 10.1016/S2215-0366(20)30255-8