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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 -
Proceedings of the National Academy of... Sep 2011There is increasing, but largely indirect, evidence pointing to an effect of commensal gut microbiota on the central nervous system (CNS). However, it is unknown whether...
There is increasing, but largely indirect, evidence pointing to an effect of commensal gut microbiota on the central nervous system (CNS). However, it is unknown whether lactic acid bacteria such as Lactobacillus rhamnosus could have a direct effect on neurotransmitter receptors in the CNS in normal, healthy animals. GABA is the main CNS inhibitory neurotransmitter and is significantly involved in regulating many physiological and psychological processes. Alterations in central GABA receptor expression are implicated in the pathogenesis of anxiety and depression, which are highly comorbid with functional bowel disorders. In this work, we show that chronic treatment with L. rhamnosus (JB-1) induced region-dependent alterations in GABA(B1b) mRNA in the brain with increases in cortical regions (cingulate and prelimbic) and concomitant reductions in expression in the hippocampus, amygdala, and locus coeruleus, in comparison with control-fed mice. In addition, L. rhamnosus (JB-1) reduced GABA(Aα2) mRNA expression in the prefrontal cortex and amygdala, but increased GABA(Aα2) in the hippocampus. Importantly, L. rhamnosus (JB-1) reduced stress-induced corticosterone and anxiety- and depression-related behavior. Moreover, the neurochemical and behavioral effects were not found in vagotomized mice, identifying the vagus as a major modulatory constitutive communication pathway between the bacteria exposed to the gut and the brain. Together, these findings highlight the important role of bacteria in the bidirectional communication of the gut-brain axis and suggest that certain organisms may prove to be useful therapeutic adjuncts in stress-related disorders such as anxiety and depression.
Topics: Amplified Fragment Length Polymorphism Analysis; Animals; Anxiety; Brain; Corticosterone; DNA, Bacterial; Depression; Emotions; Fever; Gene Expression; Host-Pathogen Interactions; In Situ Hybridization; Lactobacillus; Male; Maze Learning; Mice; Mice, Inbred BALB C; Motor Activity; RNA, Messenger; Receptors, GABA; Receptors, GABA-A; Receptors, GABA-B; Species Specificity; Vagotomy; Vagus Nerve
PubMed: 21876150
DOI: 10.1073/pnas.1102999108 -
Neuropharmacology Jul 2018Metabotropic GABA receptor is a G protein-coupled receptor (GPCR) that mediates slow and prolonged inhibitory neurotransmission in the brain. It functions as a... (Review)
Review
Metabotropic GABA receptor is a G protein-coupled receptor (GPCR) that mediates slow and prolonged inhibitory neurotransmission in the brain. It functions as a constitutive heterodimer composed of the GABA and GABA subunits. Each subunit contains three domains; the extracellular Venus flytrap module, seven-helix transmembrane region and cytoplasmic tail. In recent years, the three-dimensional structures of GABA receptor extracellular and intracellular domains have been elucidated. These structures reveal the molecular basis of ligand recognition, receptor heterodimerization and receptor activation. Here we provide a brief review of the GABA receptor structures, with an emphasis on describing the different ligand-bound states of the receptor. We will also compare these with the known structures of related GPCRs to shed light on the molecular mechanisms of activation and regulation in the GABA system, as well as GPCR dimers in general. This article is part of the "Special Issue Dedicated to Norman G. Bowery".
Topics: Humans; Protein Conformation; Receptors, GABA-B
PubMed: 29031577
DOI: 10.1016/j.neuropharm.2017.10.011 -
Journal of Integrative Neuroscience Mar 2021γ-Aminobutyric acid type A receptors (GABARs) are GABA gated heteropentameric chloride channels responsible for the adult brain's primary inhibition. In specific brain... (Review)
Review
γ-Aminobutyric acid type A receptors (GABARs) are GABA gated heteropentameric chloride channels responsible for the adult brain's primary inhibition. In specific brain cells, such as in the hippocampus, one of the subtypes of GABARs, the δ subunit containing GABARs (δ-GABARs), is predominantly expressed and located in extrasynaptic or perisynaptic positions. δ-GABARs mediate a slow constant inhibitory current called tonic inhibition. While δ-GABARs and tonic inhibition is critical for the excitability of single neurons, accumulating data suggest that the function of δ-GABARs are broader and includes an integrative role in the network oscillations. While these open new horizons on the neurobiology of δ-GABARs, the complexity continues to challenge the analysis of GABARs and their subtypes. This review will summarize the current knowledge of molecular, cellular and physiological characteristics of δ-GABARs during health and disease.
Topics: Animals; Hippocampus; Humans; Neural Inhibition; Receptors, GABA-A
PubMed: 33834705
DOI: 10.31083/j.jin.2021.01.284 -
Experimental Biology and Medicine... Oct 2021γ-aminobutyric acid or GABA is an amino acid that functionally acts as a neurotransmitter and is critical to neurotransmission. GABA is also a metabolite in the Krebs... (Review)
Review
γ-aminobutyric acid or GABA is an amino acid that functionally acts as a neurotransmitter and is critical to neurotransmission. GABA is also a metabolite in the Krebs cycle. It is therefore unsurprising that GABA and its receptors are also present outside of the central nervous system, including in immune cells. This observation suggests that GABAergic signaling impacts events beyond brain function and possibly human health beyond neurological disorders. Indeed, GABA receptor subunits are expressed in pathological disease states, including in disparate cancers. The role that GABA and its receptors may play in cancer development and progression remains unclear. If, however, those cancers have functional GABA receptors that participate in GABAergic signaling, it raises an important question whether these signaling pathways might be targetable for therapeutic benefit. Herein we summarize the effects of modulating Type-A GABA receptor signaling in various cancers and highlight how Type-A GABA receptors could emerge as a novel therapeutic target in cancer.
Topics: Animals; Humans; Neoplasms; Receptors, GABA-A; Signal Transduction; gamma-Aminobutyric Acid
PubMed: 34649481
DOI: 10.1177/15353702211032549 -
Neuroscience Bulletin Jul 2021GABA is the main inhibitory neurotransmitter in the CNS acting at two distinct types of receptor: ligand-gated ionotropic GABA receptors and G protein-coupled... (Review)
Review
GABA is the main inhibitory neurotransmitter in the CNS acting at two distinct types of receptor: ligand-gated ionotropic GABA receptors and G protein-coupled metabotropic GABA receptors, thus mediating fast and slow inhibition of excitability at central synapses. GABAergic signal transmission has been intensively studied in neurons in contrast to oligodendrocytes and their precursors (OPCs), although the latter express both types of GABA receptor. Recent studies focusing on interneuron myelination and interneuron-OPC synapses have shed light on the importance of GABA signaling in the oligodendrocyte lineage. In this review, we start with a short summary on GABA itself and neuronal GABAergic signaling. Then, we elaborate on the physiological role of GABA receptors within the oligodendrocyte lineage and conclude with a description of these receptors as putative targets in treatments of CNS diseases.
Topics: Neurons; Oligodendroglia; Receptors, GABA; Receptors, GABA-A; Synapses
PubMed: 33928492
DOI: 10.1007/s12264-021-00693-w -
Molecular Pharmacology Jul 2015The advent of whole exome/genome sequencing and the technology-driven reduction in the cost of next-generation sequencing as well as the introduction of... (Review)
Review
The advent of whole exome/genome sequencing and the technology-driven reduction in the cost of next-generation sequencing as well as the introduction of diagnostic-targeted sequencing chips have resulted in an unprecedented volume of data directly linking patient genomic variability to disorders of the brain. This information has the potential to transform our understanding of neurologic disorders by improving diagnoses, illuminating the molecular heterogeneity underlying diseases, and identifying new targets for therapeutic treatment. There is a strong history of mutations in GABA receptor genes being involved in neurologic diseases, particularly the epilepsies. In addition, a substantial number of variants and mutations have been found in GABA receptor genes in patients with autism, schizophrenia, and addiction, suggesting potential links between the GABA receptors and these conditions. A new and unexpected outcome from sequencing efforts has been the surprising number of mutations found in glutamate receptor subunits, with the GRIN2A gene encoding the GluN2A N-methyl-d-aspartate receptor subunit being most often affected. These mutations are associated with multiple neurologic conditions, for which seizure disorders comprise the largest group. The GluN2A subunit appears to be a locus for epilepsy, which holds important therapeutic implications. Virtually all α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor mutations, most of which occur within GRIA3, are from patients with intellectual disabilities, suggesting a link to this condition. Similarly, the most common phenotype for kainate receptor variants is intellectual disability. Herein, we summarize the current understanding of disease-associated mutations in ionotropic GABA and glutamate receptor families, and discuss implications regarding the identification of human mutations and treatment of neurologic diseases.
Topics: Binding Sites; Central Nervous System Agents; Genetic Predisposition to Disease; Genetic Variation; Humans; Nervous System Diseases; Protein Structure, Tertiary; Receptors, GABA; Receptors, Ionotropic Glutamate
PubMed: 25904555
DOI: 10.1124/mol.115.097998 -
Signal Transduction and Targeted Therapy Oct 2022Maintaining a proper balance between the glutamate receptor-mediated neuronal excitation and the A type of GABA receptor (GABAR) mediated inhibition is essential for...
Maintaining a proper balance between the glutamate receptor-mediated neuronal excitation and the A type of GABA receptor (GABAR) mediated inhibition is essential for brain functioning; and its imbalance contributes to the pathogenesis of many brain disorders including neurodegenerative diseases and mental illnesses. Here we identify a novel glutamate-GABAR interaction mediated by a direct glutamate binding of the GABAR. In HEK293 cells overexpressing recombinant GABARs, glutamate and its analog ligands, while producing no current on their own, potentiate GABA-evoked currents. This potentiation is mediated by a direct binding at a novel glutamate binding pocket located at the α/β subunit interface of the GABAR. Moreover, the potentiation does not require the presence of a γ subunit, and in fact, the presence of γ subunit significantly reduces the potency of the glutamate potentiation. In addition, the glutamate-mediated allosteric potentiation occurs on native GABARs in rat neurons maintained in culture, as evidenced by the potentiation of GABAR-mediated inhibitory postsynaptic currents and tonic currents. Most importantly, we found that genetic impairment of this glutamate potentiation in knock-in mice resulted in phenotypes of increased neuronal excitability, including decreased thresholds to noxious stimuli and increased seizure susceptibility. These results demonstrate a novel cross-talk between excitatory transmitter glutamate and inhibitory GABAR. Such a rapid and short feedback loop between the two principal excitatory and inhibitory neurotransmission systems may play a critical homeostatic role in fine-tuning the excitation-inhibition balance (E/I balance), thereby maintaining neuronal excitability in the mammalian brain under both physiological and pathological conditions.
Topics: Animals; Brain; Glutamic Acid; HEK293 Cells; Humans; Mammals; Mice; Rats; Receptors, GABA; Receptors, GABA-A; gamma-Aminobutyric Acid
PubMed: 36184627
DOI: 10.1038/s41392-022-01148-y