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Pharmacology and Neurobiology of GABA Receptors

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (30 November 2019) | Viewed by 45918

Special Issue Editor

Texas A&M University College of Medicine, Bryan, TX, USA
Interests: GABA; IPSC; tonic currents; benzodiazepines, neurosteroids, epilepsy; sleep; brain injury; organophosphates; sex differences

Special Issue Information

Dear Colleagues,

We are pleased to announce a Special Issue of IJMS on the “Pharmacology and Neurobiology of GABA Receptors”, which will publish research and review articles including recent advances in this field. g-Aminobutyric acid (GABA) is the principal inhibitory neurotransmitter in the brain. GABAergic neurons (~30% of total neurons) play a key role in regulating neuronal circuits and therefore dysfunction of this system results in neurological and mental disorders including epilepsy, anxiety and insomnia. GABA activates two major classes of receptors: GABA-A (heteropentameric ligand-gated chloride channels) and GABA-B receptors (heterodimeric G-protein coupled receptors). The GABA-A receptor mediates synaptic (phasic) and extrasynaptic (tonic) inhibition. It is the prolific target for a variety of clinical, recreational and experimental drugs, including benzodiazepines, barbiturates, neurosteroids, anesthetics, and ethanol. Agonists of GABA-B receptors are useful muscle relaxants. Pharmacological tools and neurobiological maps continue to develop for a greater understanding of GABA receptors at the molecular level. Recent advancements in the crystal structure of GABA receptors have provided unprecedented opportunities to develop improved drugs that better target these receptors for the treatment of neurological and psychiatric conditions. Submissions dealing with a broad array of topics on GABA receptors are welcome.

Prof. D. Samba Reddy
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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Keywords

  • GABA
  • interneurons
  • tonic inhibition
  • epilepsy
  • sleep
  • anxiety
  • anesthetic
  • neurosteroid
  • benzodiazepine
  • ethanol
  • treatment
  • antidote

Published Papers (9 papers)

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Research

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22 pages, 3439 KiB  
Article
Alpha-1 Adrenergic Receptors Modulate Glutamate and GABA Neurotransmission onto Ventral Tegmental Dopamine Neurons during Cocaine Sensitization
by Maria Carolina Velasquez-Martinez, Bermary Santos-Vera, Maria E. Velez-Hernandez, Rafael Vazquez-Torres and Carlos A. Jimenez-Rivera
Int. J. Mol. Sci. 2020, 21(3), 790; https://doi.org/10.3390/ijms21030790 - 25 Jan 2020
Cited by 7 | Viewed by 4781
Abstract
The ventral tegmental area (VTA) plays an important role in the reward and motivational processes that facilitate the development of drug addiction. Presynaptic α1-AR activation modulates glutamate and Gamma-aminobutyric acid (GABA) release. This work elucidates the role of VTA presynaptic α1-ARs and their [...] Read more.
The ventral tegmental area (VTA) plays an important role in the reward and motivational processes that facilitate the development of drug addiction. Presynaptic α1-AR activation modulates glutamate and Gamma-aminobutyric acid (GABA) release. This work elucidates the role of VTA presynaptic α1-ARs and their modulation on glutamatergic and GABAergic neurotransmission during cocaine sensitization. Excitatory and inhibitory currents (EPSCs and IPSCs) measured by a whole cell voltage clamp show that α1-ARs activation increases EPSCs amplitude after 1 day of cocaine treatment but not after 5 days of cocaine injections. The absence of a pharmacological response to an α1-ARs agonist highlights the desensitization of the receptor after repeated cocaine administration. The desensitization of α1-ARs persists after a 7-day withdrawal period. In contrast, the modulation of α1-ARs on GABA neurotransmission, shown by decreases in IPSCs’ amplitude, is not affected by acute or chronic cocaine injections. Taken together, these data suggest that α1-ARs may enhance DA neuronal excitability after repeated cocaine administration through the reduction of GABA inhibition onto VTA dopamine (DA) neurons even in the absence of α1-ARs’ function on glutamate release and protein kinase C (PKC) activation. α1-AR modulatory changes in cocaine sensitization increase our knowledge of the role of the noradrenergic system in cocaine addiction and may provide possible avenues for therapeutics. Full article
(This article belongs to the Special Issue Pharmacology and Neurobiology of GABA Receptors)
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11 pages, 1683 KiB  
Article
GABAA Receptor-Mediated Currents and Hormone mRNAs in Cells Expressing More Than One Hormone Transcript in Intact Human Pancreatic Islets
by Sergiy V. Korol, Zhe Jin and Bryndis Birnir
Int. J. Mol. Sci. 2020, 21(2), 600; https://doi.org/10.3390/ijms21020600 - 17 Jan 2020
Cited by 2 | Viewed by 2386
Abstract
In pancreatic islets, the major cell-types are α, β and δ cells. The γ-aminobutyric acid (GABA) signalling system is expressed in human pancreatic islets. In single hormone transcript-expressing cells, we have previously characterized the functional properties of islet GABAA receptors (iGABAA [...] Read more.
In pancreatic islets, the major cell-types are α, β and δ cells. The γ-aminobutyric acid (GABA) signalling system is expressed in human pancreatic islets. In single hormone transcript-expressing cells, we have previously characterized the functional properties of islet GABAA receptors (iGABAARs). Here, we extended these studies to islet cells expressing mRNAs for more than one hormone and sought for correlation between iGABAAR activity level and relative mRNA expression ratio. The single-cell RT-PCR in combination with the patch-clamp current recordings was used to examine functional properties of iGABAARs in the multiple hormone mRNA-expressing cells. We detected cells expressing double (α/β, α/δ, β/δ cell-types) and triple (α/β/δ cell-type) hormone transcripts. The most common mixed-identity cell-type was the α/β group where the cells could be grouped into β- and α-like subgroups. The β-like cells had low GCG/INS expression ratio (<0.6) and significantly higher frequency of iGABAAR single-channel openings than the α-like cells where the GCG/INS expression ratio was high (>1.2). The hormone expression levels and iGABAAR single-channel characteristics varied in the α/β/δ cell-type. Clearly, multiple hormone transcripts can be expressed in islet cells whereas iGABAAR single-channel functional properties appear to be α or β cell specific. Full article
(This article belongs to the Special Issue Pharmacology and Neurobiology of GABA Receptors)
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14 pages, 1911 KiB  
Article
Comprehensive Analysis of GABAA-A1R Developmental Alterations in Rett Syndrome: Setting the Focus for Therapeutic Targets in the Time Frame of the Disease
by Alfonso Oyarzabal, Clara Xiol, Alba Aina Castells, Cristina Grau, Mar O’Callaghan, Guerau Fernández, Soledad Alcántara, Mercè Pineda, Judith Armstrong, Xavier Altafaj and Angels García-Cazorla
Int. J. Mol. Sci. 2020, 21(2), 518; https://doi.org/10.3390/ijms21020518 - 14 Jan 2020
Cited by 8 | Viewed by 3718
Abstract
Rett syndrome, a serious neurodevelopmental disorder, has been associated with an altered expression of different synaptic-related proteins and aberrant glutamatergic and γ-aminobutyric acid (GABA)ergic neurotransmission. Despite its severity, it lacks a therapeutic option. Through this work we aimed to define the relationship between [...] Read more.
Rett syndrome, a serious neurodevelopmental disorder, has been associated with an altered expression of different synaptic-related proteins and aberrant glutamatergic and γ-aminobutyric acid (GABA)ergic neurotransmission. Despite its severity, it lacks a therapeutic option. Through this work we aimed to define the relationship between MeCP2 and GABAA.-A1 receptor expression, emphasizing the time dependence of such relationship. For this, we analyzed the expression of the ionotropic receptor subunit in different MeCP2 gene-dosage and developmental conditions, in cells lines, and in primary cultured neurons, as well as in different developmental stages of a Rett mouse model. Further, RNAseq and systems biology analysis was performed from post-mortem brain biopsies of Rett patients. We observed that the modulation of the MeCP2 expression in cellular models (both Neuro2a (N2A) cells and primary neuronal cultures) revealed a MeCP2 positive effect on the GABAA.-A1 receptor subunit expression, which did not occur in other proteins such as KCC2 (Potassium-chloride channel, member 5). In the Mecp2+/− mouse brain, both the KCC2 and GABA subunits expression were developmentally regulated, with a decreased expression during the pre-symptomatic stage, while the expression was variable in the adult symptomatic mice. Finally, the expression of the gamma-aminobutyric acid (GABA) receptor-related synaptic proteins from the postmortem brain biopsies of two Rett patients was evaluated, specifically revealing the GABA A1R subunit overexpression. The identification of the molecular changes along with the Rett syndrome prodromic stages strongly endorses the importance of time frame when addressing this disease, supporting the need for a neurotransmission-targeted early therapeutic intervention. Full article
(This article belongs to the Special Issue Pharmacology and Neurobiology of GABA Receptors)
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20 pages, 5011 KiB  
Article
GABAA Receptor Ligands Often Interact with Binding Sites in the Transmembrane Domain and in the Extracellular Domain—Can the Promiscuity Code Be Cracked?
by Maria Teresa Iorio, Florian Daniel Vogel, Filip Koniuszewski, Petra Scholze, Sabah Rehman, Xenia Simeone, Michael Schnürch, Marko D. Mihovilovic and Margot Ernst
Int. J. Mol. Sci. 2020, 21(1), 334; https://doi.org/10.3390/ijms21010334 - 03 Jan 2020
Cited by 17 | Viewed by 4705
Abstract
Many allosteric binding sites that modulate gamma aminobutyric acid (GABA) effects have been described in heteropentameric GABA type A (GABAA) receptors, among them sites for benzodiazepines, pyrazoloquinolinones and etomidate. Diazepam not only binds at the high affinity extracellular “canonical” site, but [...] Read more.
Many allosteric binding sites that modulate gamma aminobutyric acid (GABA) effects have been described in heteropentameric GABA type A (GABAA) receptors, among them sites for benzodiazepines, pyrazoloquinolinones and etomidate. Diazepam not only binds at the high affinity extracellular “canonical” site, but also at sites in the transmembrane domain. Many ligands of the benzodiazepine binding site interact also with homologous sites in the extracellular domain, among them the pyrazoloquinolinones that exert modulation at extracellular α+/β− sites. Additional interaction of this chemotype with the sites for etomidate has also been described. We have recently described a new indole-based scaffold with pharmacophore features highly similar to pyrazoloquinolinones as a novel class of GABAA receptor modulators. Contrary to what the pharmacophore overlap suggests, the ligand presented here behaves very differently from the identically substituted pyrazoloquinolinone. Structural evidence demonstrates that small changes in pharmacophore features can induce radical changes in ligand binding properties. Analysis of published data reveals that many chemotypes display a strong tendency to interact promiscuously with binding sites in the transmembrane domain and others in the extracellular domain of the same receptor. Further structural investigations of this phenomenon should enable a more targeted path to less promiscuous ligands, potentially reducing side effect liabilities. Full article
(This article belongs to the Special Issue Pharmacology and Neurobiology of GABA Receptors)
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18 pages, 4266 KiB  
Article
Depression, GABA, and Age Correlate with Plasma Levels of Inflammatory Markers
by Amol K. Bhandage, Janet L. Cunningham, Zhe Jin, Qiujin Shen, Santiago Bongiovanni, Sergiy V. Korol, Mikaela Syk, Masood Kamali-Moghaddam, Lisa Ekselius and Bryndis Birnir
Int. J. Mol. Sci. 2019, 20(24), 6172; https://doi.org/10.3390/ijms20246172 - 06 Dec 2019
Cited by 17 | Viewed by 5502
Abstract
Immunomodulation is increasingly being recognised as a part of mental diseases. Here, we examined whether levels of immunological protein markers changed with depression, age, or the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). An analysis of plasma samples from patients with a major depressive episode [...] Read more.
Immunomodulation is increasingly being recognised as a part of mental diseases. Here, we examined whether levels of immunological protein markers changed with depression, age, or the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). An analysis of plasma samples from patients with a major depressive episode and control blood donors (CBD) revealed the expression of 67 inflammatory markers. Thirteen of these markers displayed augmented levels in patients compared to CBD. Twenty-one markers correlated with the age of the patients, whereas 10 markers correlated with the age of CBD. Interestingly, CST5 and CDCP1 showed the strongest correlation with age in the patients and CBD, respectively. IL-18 was the only marker that correlated with the MADRS-S scores of the patients. Neuronal growth factors (NGFs) were significantly enhanced in plasma from the patients, as was the average plasma GABA concentration. GABA modulated the release of seven cytokines in anti-CD3-stimulated peripheral blood mononuclear cells (PBMCs) from the patients. The study reveals significant changes in the plasma composition of small molecules during depression and identifies potential peripheral biomarkers of the disease. Full article
(This article belongs to the Special Issue Pharmacology and Neurobiology of GABA Receptors)
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12 pages, 2363 KiB  
Article
Effects of Diazepam on Low-Frequency and High-Frequency Electrocortical γ-Power Mediated by α1- and α2-GABAA Receptors
by Julian I. Hofmann, Cornelius Schwarz, Uwe Rudolph and Bernd Antkowiak
Int. J. Mol. Sci. 2019, 20(14), 3486; https://doi.org/10.3390/ijms20143486 - 16 Jul 2019
Cited by 8 | Viewed by 4083
Abstract
Patterns of spontaneous electric activity in the cerebral cortex change upon administration of benzodiazepines. Here we are testing the hypothesis that the prototypical benzodiazepine, diazepam, affects spectral power density in the low (20–50 Hz) and high (50–90 Hz) γ-band by targeting GABAA [...] Read more.
Patterns of spontaneous electric activity in the cerebral cortex change upon administration of benzodiazepines. Here we are testing the hypothesis that the prototypical benzodiazepine, diazepam, affects spectral power density in the low (20–50 Hz) and high (50–90 Hz) γ-band by targeting GABAA receptors harboring α1- and α2-subunits. Local field potentials (LFPs) and action potentials were recorded in the barrel cortex of wild type mice and two mutant strains in which the drug exclusively acted via GABAA receptors containing either α1- (DZα1-mice) or α2-subunits (DZα2-mice). In wild type mice, diazepam enhanced low γ-power. This effect was also evident in DZα2-mice, while diazepam decreased low γ-power in DZα1-mice. Diazepam increased correlated local LFP-activity in wild type animals and DZα2- but not in DZα1-mice. In all genotypes, spectral power density in the high γ-range and multi-unit action potential activity declined upon diazepam administration. We conclude that diazepam modifies low γ-power in opposing ways via α1- and α2-GABAA receptors. The drug’s boosting effect involves α2-receptors and an increase in local intra-cortical synchrony. Furthermore, it is important to make a distinction between high- and low γ-power when evaluating the effects of drugs that target GABAA receptors. Full article
(This article belongs to the Special Issue Pharmacology and Neurobiology of GABA Receptors)
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Review

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15 pages, 641 KiB  
Review
Phytocannabinoids in Neurological Diseases: Could They Restore a Physiological GABAergic Transmission?
by Pierangelo Cifelli, Gabriele Ruffolo, Eleonora De Felice, Veronica Alfano, Erwin Alexander van Vliet, Eleonora Aronica and Eleonora Palma
Int. J. Mol. Sci. 2020, 21(3), 723; https://doi.org/10.3390/ijms21030723 - 22 Jan 2020
Cited by 31 | Viewed by 9100
Abstract
γ-Aminobutyric acid type A receptors (GABAARs) are the main inhibitory mediators in the central nervous system (CNS). GABAARs are pentameric ligand gated ion channels, and the main subunit composition is usually 2α2βγ, with various isotypes assembled within a set [...] Read more.
γ-Aminobutyric acid type A receptors (GABAARs) are the main inhibitory mediators in the central nervous system (CNS). GABAARs are pentameric ligand gated ion channels, and the main subunit composition is usually 2α2βγ, with various isotypes assembled within a set of 19 different subunits. The inhibitory function is mediated by chloride ion movement across the GABAARs, activated by synaptic GABA release, reducing neuronal excitability in the adult CNS. Several studies highlighted the importance of GABA-mediated transmission during neuro-development, and its involvement in different neurological and neurodevelopmental diseases, from anxiety to epilepsy. However, while it is well known how different classes of drugs are able to modulate the GABAARs function (benzodiazepines, barbiturates, neurosteroids, alcohol), up to now little is known about GABAARs and cannabinoids interaction in the CNS. Endocannabinoids and phytocannabinoids are lately emerging as a new class of promising drugs for a wide range of neurological conditions, but their safety as medication, and their mechanisms of action are still to be fully elucidated. In this review, we will focus our attention on two of the most promising molecules (Δ9-tetrahydrocannabinol; Δ9-THC and cannabidiol; CBD) of this new class of drugs and their possible mechanism of action on GABAARs. Full article
(This article belongs to the Special Issue Pharmacology and Neurobiology of GABA Receptors)
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22 pages, 974 KiB  
Review
TGF-β/Smad3 Signalling Modulates GABA Neurotransmission: Implications in Parkinson’s Disease
by Mª Dolores Muñoz, Nerea de la Fuente and Amelia Sánchez-Capelo
Int. J. Mol. Sci. 2020, 21(2), 590; https://doi.org/10.3390/ijms21020590 - 16 Jan 2020
Cited by 27 | Viewed by 5788
Abstract
γ-Aminobutiryc acid (GABA) is found extensively in different brain nuclei, including parts involved in Parkinson’s disease (PD), such as the basal ganglia and hippocampus. In PD and in different models of the disorder, an increase in GABA neurotransmission is observed and may promote [...] Read more.
γ-Aminobutiryc acid (GABA) is found extensively in different brain nuclei, including parts involved in Parkinson’s disease (PD), such as the basal ganglia and hippocampus. In PD and in different models of the disorder, an increase in GABA neurotransmission is observed and may promote bradykinesia or L-Dopa-induced side-effects. In addition, proteins involved in GABAA receptor (GABAAR) trafficking, such as GABARAP, Trak1 or PAELR, may participate in the aetiology of the disease. TGF-β/Smad3 signalling has been associated with several pathological features of PD, such as dopaminergic neurodegeneration; reduction of dopaminergic axons and dendrites; and α-synuclein aggregation. Moreover, TGF-β/Smad3 intracellular signalling was recently shown to modulate GABA neurotransmission in the context of parkinsonism and cognitive alterations. This review provides a summary of GABA neurotransmission and TGF-β signalling; their implications in PD; and the regulation of GABA neurotransmission by TGF-β/Smad3. There appear to be new possibilities to develop therapeutic approaches for the treatment of PD using GABA modulators. Full article
(This article belongs to the Special Issue Pharmacology and Neurobiology of GABA Receptors)
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13 pages, 1627 KiB  
Review
Molecular and Regulatory Mechanisms of Desensitization and Resensitization of GABAA Receptors with a Special Reference to Propofol/Barbiturate
by Youngnam Kang, Mitsuru Saito and Hiroki Toyoda
Int. J. Mol. Sci. 2020, 21(2), 563; https://doi.org/10.3390/ijms21020563 - 15 Jan 2020
Cited by 10 | Viewed by 4346
Abstract
It is known that desensitization of GABAA receptor (GABAAR)-mediated currents is paradoxically correlated with the slowdown of their deactivation, i.e., resensitization. It has been shown that an upregulation of calcineurin enhances the desensitization of GABAAR-mediated currents but paradoxically [...] Read more.
It is known that desensitization of GABAA receptor (GABAAR)-mediated currents is paradoxically correlated with the slowdown of their deactivation, i.e., resensitization. It has been shown that an upregulation of calcineurin enhances the desensitization of GABAAR-mediated currents but paradoxically prolongs the decay phase of inhibitory postsynaptic currents/potentials without appreciable diminution of their amplitudes. The paradoxical correlation between desensitization and resensitization of GABAAR-mediated currents can be more clearly seen in response to a prolonged application of GABA to allow more desensitization, instead of brief pulse used in previous studies. Indeed, hump-like GABAAR currents were produced after a strong desensitization at the offset of a prolonged puff application of GABA in pyramidal cells of the barrel cortex, in which calcineurin activity was enhanced by deleting phospholipase C-related catalytically inactive proteins to enhance the desensitization/resensitization of GABAAR-mediated currents. Hump-like GABAAR currents were also evoked at the offset of propofol or barbiturate applications in hippocampal or sensory neurons, but not GABA applications. Propofol and barbiturate are useful to treat benzodiazepine/alcohol withdrawal syndrome, suggesting that regulatory mechanisms of desensitization/resensitization of GABAAR-mediated currents are important in understanding benzodiazepine/alcohol withdrawal syndrome. In this review, we will discuss the molecular and regulatory mechanisms underlying the desensitization and resensitization of GABAAR-mediated currents and their functional significances. Full article
(This article belongs to the Special Issue Pharmacology and Neurobiology of GABA Receptors)
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