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Biomolecules
Special Issues
GABA Receptors in Pharmacology and Neurobiology
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GABA Receptors in Pharmacology and Neurobiology

A special issue of Biomolecules (ISSN 2218-273X).

Deadline for manuscript submissions: closed (30 November 2022) | Viewed by 8408

Special Issue Editor

Prof. Dr. Katarina Vukojević

E-Mail Website
Guest Editor
Department of Anatomy, Histology and Embryology, University of Split School of Medicine, Šoltanska 2, 21000 Split, Croatia
Interests: kidney development; congenital anomalies of kidney; next-generation sequencing; chronic kidney diseases; precision medicine; diabetic nephropathy
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

We are announcing a Special Issue of Biomolecules on the “GABA Receptors in Pharmacology and Neurobiology” in order to highlight the importance of GABA-mediated transmission during neurodevelopment and different psychiatric and neurological disorders. γ-Aminobutyric acid type A receptors are the main inhibitory mediators in the central nervous system, and are seen as promising therapeutical targets since they mediate the rapid synaptic as well as the slow extrasynaptic inhibitory neurotransmission. Agonists of GABA-B receptors are useful muscle relaxants and antinociceptive in acute pain models. GABAergic neurons are the key players in regulating neuronal circuits, and deficits in GABAergic signalling underlie the pathophysiology of several psychiatric and neurological conditions from anxiety and insomnia to epilepsy. Thus, elucidating the pharmacological and neurobiological potential and molecular properties of GABA receptors as well as developing more selective therapeutical targeting drugs with less side effects remain a challenge in modern drug discovery. Submissions dealing with different perspectives of GABA receptors are welcome, and we look forward to reading your contributions.

Prof. Dr. Katarina Vukojević
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.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomolecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • GABA receptors
  • chloride channels
  • interneurons
  • general anaesthetics
  • tonic inhibition
  • epilepsy
  • sleep
  • anxiolytics
  • anxiety
  • anaesthetic
  • neurosteroid
  • benzodiazepine
  • alcohol
  • antidote
  • treatment

Published Papers (4 papers)

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Research

20 pages, 2435 KiB  
Article
GABA-A Alpha 2/3 but Not Alpha 1 Receptor Subunit Ligand Inhibits Harmaline and Pimozide-Induced Tremor in Rats
by Barbara Kosmowska, Martyna Paleczna, Dominika Biała, Justyna Kadłuczka, Jadwiga Wardas, Jeffrey M. Witkin, James M. Cook, Dishary Sharmin, Monika Marcinkowska and Katarzyna Z. Kuter
Biomolecules 2023, 13(2), 197; https://0-doi-org.brum.beds.ac.uk/10.3390/biom13020197 - 18 Jan 2023
Cited by 2 | Viewed by 2420
Abstract
Treatment of tremors, such as in essential tremor (ET) and Parkinson’s disease (PD) is mostly ineffective. Exact tremor pathomechanisms are unknown and relevant animal models are missing. GABA-A receptor is a target for tremorolytic medications, but current non-selective drugs produce side effects and [...] Read more.
Treatment of tremors, such as in essential tremor (ET) and Parkinson’s disease (PD) is mostly ineffective. Exact tremor pathomechanisms are unknown and relevant animal models are missing. GABA-A receptor is a target for tremorolytic medications, but current non-selective drugs produce side effects and have safety liabilities. The aim of this study was a search for GABA-A subunit-specific tremorolytics using different tremor-generating mechanisms. Two selective positive allosteric modulators (PAMs) were tested. Zolpidem, targeting GABA-A α1, was not effective in models of harmaline-induced ET, pimozide- or tetrabenazine-induced tremulous jaw movements (TJMs), while the novel GABA-A α2/3 selective MP-III-024 significantly reduced both the harmaline-induced ET tremor and pimozide-induced TJMs. While zolpidem decreased the locomotor activity of the rats, MP-III-024 produced small increases. These results provide important new clues into tremor suppression mechanisms initiated by the enhancement of GABA-driven inhibition in pathways controlled by α2/3 but not α1 containing GABA-A receptors. Tremor suppression by MP-III-024 provides a compelling reason to consider selective PAMs targeting α2/3-containing GABA-A receptors as novel therapeutic drug targets for ET and PD-associated tremor. The possibility of the improved tolerability and safety of this mechanism over non-selective GABA potentiation provides an additional rationale to further pursue the selective α2/3 hypothesis. Full article
(This article belongs to the Special Issue GABA Receptors in Pharmacology and Neurobiology)
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17 pages, 2670 KiB  
Article
Developmental Inhibitory Changes in the Primary Somatosensory Cortex of the Stargazer Mouse Model of Absence Epilepsy
by Muhammad Hassan, David R. Grattan and Beulah Leitch
Biomolecules 2023, 13(1), 186; https://0-doi-org.brum.beds.ac.uk/10.3390/biom13010186 - 16 Jan 2023
Viewed by 1676
Abstract
Childhood absence epilepsy seizures arise in the cortico-thalamocortical network due to multiple cellular and molecular mechanisms, which are still under investigation. Understanding the precise mechanisms is imperative given that treatment fails in ~30% of patients while adverse neurological sequelae remain common. Impaired GABAergic [...] Read more.
Childhood absence epilepsy seizures arise in the cortico-thalamocortical network due to multiple cellular and molecular mechanisms, which are still under investigation. Understanding the precise mechanisms is imperative given that treatment fails in ~30% of patients while adverse neurological sequelae remain common. Impaired GABAergic neurotransmission is commonly reported in research models investigating these mechanisms. Recently, we reported a region-specific reduction in the whole-tissue and synaptic GABAA receptor (GABAAR) α1 subunit and an increase in whole-tissue GAD65 in the primary somatosensory cortex (SoCx) of the adult epileptic stargazer mouse compared with its non-epileptic (NE) littermate. The current study investigated whether these changes occurred prior to the onset of seizures on postnatal days (PN) 17–18, suggesting a causative role. Synaptic and cytosolic fractions were biochemically isolated from primary SoCx lysates followed by semiquantitative Western blot analyses for GABAAR α1 and GAD65. We found no significant changes in synaptic GABAAR α1 and cytosolic GAD65 in the primary SoCx of the stargazer mice at the critical developmental stages of PN 7–9, 13–15, and 17–18. This indicates that altered levels of GABAAR α1 and GAD65 in adult mice do not directly contribute to the initial onset of absence seizures but are a later consequence of seizure activity. Full article
(This article belongs to the Special Issue GABA Receptors in Pharmacology and Neurobiology)
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11 pages, 8083 KiB  
Article
Residues in the 1st Transmembrane-Spanning Helix Are Important for GABAAρ Receptor Function
by Kate M. Crowther, Susanne M. Mesoy and Sarah C. R. Lummis
Biomolecules 2022, 12(9), 1251; https://0-doi-org.brum.beds.ac.uk/10.3390/biom12091251 - 07 Sep 2022
Cited by 1 | Viewed by 1281
Abstract
GABAAρ receptors are a subfamily of the GABAA receptor family of pentameric ligand-gated ion channels (pLGICs). Each subunit has a common structure, including a transmembrane domain of four α-helices (M1–M4). The aim of this study was to identify important M1 [...] Read more.
GABAAρ receptors are a subfamily of the GABAA receptor family of pentameric ligand-gated ion channels (pLGICs). Each subunit has a common structure, including a transmembrane domain of four α-helices (M1–M4). The aim of this study was to identify important M1 residues in the GABAAρ receptor (GABAAρR), using mutagenesis and functional assays combined with bioinformatic approaches. Alanine substitution of 12 of the 23 M1 residues yielded receptors with altered functional parameters, indicating these residues contribute to GABAAρR function. Further mutations reveal the properties that are important for function in critical residues, and, using a GABAAρR homology model, we suggest amino acid interactions that could be important. Phylogenetic analysis comparing GABAAR and other pLGICs subunits reveals most M1 residue properties linked to GABAAρR function are ancestrally ancient, but some are more recent acquisitions. Multiple sequence alignment of M1 residues across GABAAR subunits reveal three residues are well conserved except in GABAAR α subunits. Substitution of ρ1 subunit residues to their α1 subunit equivalents showed one alters functional parameters. Overall, the data provide a comprehensive picture of M1 residues that contribute to GABAAρR function, and illustrate how they might do so. Full article
(This article belongs to the Special Issue GABA Receptors in Pharmacology and Neurobiology)
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10 pages, 931 KiB  
Article
Effects of Risperidone and Prenatal Poly I:C Exposure on GABAA Receptors and AKT-GSK3β Pathway in the Ventral Tegmental Area of Female Juvenile Rats
by Shiyan Chen, Jiamei Lian, Yueqing Su and Chao Deng
Biomolecules 2022, 12(5), 732; https://0-doi-org.brum.beds.ac.uk/10.3390/biom12050732 - 23 May 2022
Cited by 2 | Viewed by 2088
Abstract
The ventral tegmental area (VTA) in the ventral midbrain is the origin of the dopaminergic neurotransmission pathways. Although GABAA receptors and AKT-GSK3β signaling are involved in the pathophysiology of mental disorders and are modulated by antipsychotics, an unmet task is to reveal [...] Read more.
The ventral tegmental area (VTA) in the ventral midbrain is the origin of the dopaminergic neurotransmission pathways. Although GABAA receptors and AKT-GSK3β signaling are involved in the pathophysiology of mental disorders and are modulated by antipsychotics, an unmet task is to reveal the pathological changes in these biomarkers and antipsychotic modulations in the VTA. Using a juvenile polyriboinosinic-polyribocytidylic acid (Poly I:C) psychiatric rat model, this study investigated the effects of adolescent risperidone treatment on GABAA receptors and AKT/GSK3β in the VTA. Pregnant female Sprague–Dawley rats were administered Poly I:C (5mg/kg; i.p) or saline at gestational day 15. Juvenile female offspring received risperidone (0.9 mg/kg, twice per day) or a vehicle from postnatal day 35 for 25 days. Poly I:C offspring had significantly decreased mRNA expression of GABAA receptor β3 subunits and glutamic acid decarboxylase (GAD2) in the VTA, while risperidone partially reversed the decreased GAD2 expression. Prenatal Poly I:C exposure led to increased expression of AKT2 and GSK3β. Risperidone decreased GABAA receptor β2/3, but increased AKT2 mRNA expression in the VTA of healthy rats. This study suggests that Poly I:C-elicited maternal immune activation and risperidone differentially modulate GABAergic neurotransmission and AKT-GSK3β signaling in the VTA of adolescent rats. Full article
(This article belongs to the Special Issue GABA Receptors in Pharmacology and Neurobiology)
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