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Biomolecules
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GABA(A) Receptors: Structure and Function
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GABA(A) Receptors: Structure and Function

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Biomacromolecules: Proteins".

Deadline for manuscript submissions: closed (30 September 2022) | Viewed by 17627

Special Issue Editor

Dr. Gustav Akk

E-Mail Website
Guest Editor
Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, USA
Interests: molecular neuropharmacology; GABA receptor; nicotinic receptor; anesthetics; sedation; synaptic transmission

Special Issue Information

Dear Colleagues,

The γ-aminobutyric acid type A (GABAA) receptor, a member of the Cys-loop superfamily of transmitter-gated ion channels, is a major ionotropic inhibitory ion channel in the brain. It is normally activated by the transmitter GABA, whose binding to the receptor leads to opening of an anion-selective channel pore, thereby influencing the excitatory–inhibitory balance of the cell. The receptor is a target for endogenous compounds such as neurosteroids that can potentiate or inhibit receptor activity, and a number of clinically relevant drugs, including benzodiazepines, propofol, and etomidate. Potentiation of GABAA receptor function contributes to anxiolysis, sedation, and anesthesia.

This Special Issue has two aims. The first is to highlight the functional properties and molecular structure of the GABAA receptor. The second focuses on the biological role of the GABAA receptor, its involvement in disease, and pharmacology of the receptor.

Dr. Gustav Akk
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

  • transmitter-gated ion channel
  • GABAA receptor
  • activation
  • modulation
  • structure
  • modeling
  • anesthetics
  • sedatives

Published Papers (6 papers)

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Research

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19 pages, 2581 KiB  
Article
Mutational Analysis of Anesthetic Binding Sites and Their Effects on GABAA Receptor Activation and Modulation by Positive Allosteric Modulators of the α7 Nicotinic Receptor
by Spencer R. Pierce, Allison L. Germann, Sophia Q. Xu, Saumith L. Menon, Marcelo O. Ortells, Hugo R. Arias and Gustav Akk
Biomolecules 2023, 13(4), 698; https://doi.org/10.3390/biom13040698 - 20 Apr 2023
Cited by 1 | Viewed by 1081
Abstract
The positive allosteric modulators (PAMs) of the α7 nicotinic receptor N-(5-Cl-2-hydroxyphenyl)-N′-[2-Cl-5-(trifluoromethyl)phenyl]-urea (NS-1738) and (E)-3-(furan-2-yl)-N-(p-tolyl)-acrylamide (PAM-2) potentiate the α1β2γ2L GABAA receptor through interactions with the classic anesthetic binding sites located at intersubunit interfaces in [...] Read more.
The positive allosteric modulators (PAMs) of the α7 nicotinic receptor N-(5-Cl-2-hydroxyphenyl)-N′-[2-Cl-5-(trifluoromethyl)phenyl]-urea (NS-1738) and (E)-3-(furan-2-yl)-N-(p-tolyl)-acrylamide (PAM-2) potentiate the α1β2γ2L GABAA receptor through interactions with the classic anesthetic binding sites located at intersubunit interfaces in the transmembrane domain of the receptor. In the present study, we employed mutational analysis to investigate in detail the involvement and contributions made by the individual intersubunit interfaces to receptor modulation by NS-1738 and PAM-2. We show that mutations to each of the anesthetic-binding intersubunit interfaces (β+/α−, α+/β−, and γ+/β−), as well as the orphan α+/γ− interface, modify receptor potentiation by NS-1738 and PAM-2. Furthermore, mutations to any single interface can fully abolish potentiation by the α7-PAMs. The findings are discussed in the context of energetic additivity and interactions between the individual binding sites. Full article
(This article belongs to the Special Issue GABA(A) Receptors: Structure and Function)
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27 pages, 4547 KiB  
Article
GABRG2 Variants Associated with Febrile Seizures
by Ciria C. Hernandez, Yanwen Shen, Ningning Hu, Wangzhen Shen, Vinodh Narayanan, Keri Ramsey, Wen He, Liping Zou and Robert L. Macdonald
Biomolecules 2023, 13(3), 414; https://doi.org/10.3390/biom13030414 - 22 Feb 2023
Cited by 4 | Viewed by 1619
Abstract
Febrile seizures (FS) are the most common form of epilepsy in children between six months and five years of age. FS is a self-limited type of fever-related seizure. However, complicated prolonged FS can lead to complex partial epilepsy. We found that among the [...] Read more.
Febrile seizures (FS) are the most common form of epilepsy in children between six months and five years of age. FS is a self-limited type of fever-related seizure. However, complicated prolonged FS can lead to complex partial epilepsy. We found that among the GABAA receptor subunit (GABR) genes, most variants associated with FS are harbored in the γ2 subunit (GABRG2). Here, we characterized the effects of eight variants in the GABAA receptor γ2 subunit on receptor biogenesis and channel function. Two-thirds of the GABRG2 variants followed the expected autosomal dominant inheritance in FS and occurred as missense and nonsense variants. The remaining one-third appeared as de novo in the affected probands and occurred only as missense variants. The loss of GABAA receptor function and dominant negative effect on GABAA receptor biogenesis likely caused the FS phenotype. In general, variants in the GABRG2 result in a broad spectrum of phenotypic severity, ranging from asymptomatic, FS, genetic epilepsy with febrile seizures plus (GEFS+), and Dravet syndrome individuals. The data presented here support the link between FS, epilepsy, and GABRG2 variants, shedding light on the relationship between the variant topological occurrence and disease severity. Full article
(This article belongs to the Special Issue GABA(A) Receptors: Structure and Function)
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17 pages, 9451 KiB  
Article
Commonly Used Therapeutics Associated with Changes in Arousal Inhibit GABAAR Activation
by Anling Kaplan, Abigail I. Nash, Amanda A. H. Freeman, Lauren G. Lewicki, David B. Rye, Lynn Marie Trotti, Asher L. Brandt and Andrew Jenkins
Biomolecules 2023, 13(2), 365; https://doi.org/10.3390/biom13020365 - 15 Feb 2023
Cited by 1 | Viewed by 2277
Abstract
GABAA receptor-positive modulators are well-known to induce sedation, sleep, and general anesthesia. Conversely, GABAA receptor negative allosteric modulators (GABAARNAMs) can increase arousal and induce seizures. Motivated by our studies with patients with hypersomnia, and our discovery that two GABA [...] Read more.
GABAA receptor-positive modulators are well-known to induce sedation, sleep, and general anesthesia. Conversely, GABAA receptor negative allosteric modulators (GABAARNAMs) can increase arousal and induce seizures. Motivated by our studies with patients with hypersomnia, and our discovery that two GABAARNAMs can restore the Excitation/Inhibition (E/I) balance in vitro and arousal in vivo, we chose to screen 11 compounds that have been reported to modulate arousal, to see if they shared a GABA-related mechanism. We determined modulation with both conventional and microfluidic patch clamp methods. We found that receptor activation was variably modulated by all 11 compounds: Rifampicin (RIF), Metronidazole (MET), Minocycline (MIN), Erythromycin (ERY), Ofloxacin (OFX), Chloroquine (CQ), Hydroxychloroquine sulfate (HCQ), Flumazenil (FLZ), Pentylenetetrazol (PTZ), (-)-Epigallocatechin Gallate (EGCG), and clarithromycin (CLR). The computational modeling of modulator–receptor interactions predicted drug action at canonical binding sites and novel orphan sites on the receptor. Our findings suggest that multiple avenues of investigation are now open to investigate large and brain-penetrant molecules for the treatment of patients with diminished CNS E/I balance. Full article
(This article belongs to the Special Issue GABA(A) Receptors: Structure and Function)
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14 pages, 1862 KiB  
Article
The Mechanism of Enantioselective Neurosteroid Actions on GABAA Receptors
by Hiroki Tateiwa, Satyanarayana M. Chintala, Ziwei Chen, Lei Wang, Fatima Amtashar, John Bracamontes, Allison L. Germann, Spencer R. Pierce, Douglas F. Covey, Gustav Akk and Alex S. Evers
Biomolecules 2023, 13(2), 341; https://doi.org/10.3390/biom13020341 - 09 Feb 2023
Cited by 6 | Viewed by 1398
Abstract
The neurosteroid allopregnanolone (ALLO) and pregnanolone (PREG), are equally effective positive allosteric modulators (PAMs) of GABAA receptors. Interestingly, the PAM effects of ALLO are strongly enantioselective, whereas those of PREG are not. This study was aimed at determining the basis for this [...] Read more.
The neurosteroid allopregnanolone (ALLO) and pregnanolone (PREG), are equally effective positive allosteric modulators (PAMs) of GABAA receptors. Interestingly, the PAM effects of ALLO are strongly enantioselective, whereas those of PREG are not. This study was aimed at determining the basis for this difference in enantioselectivity. The oocyte electrophysiology studies showed that ent-ALLO potentiates GABA-elicited currents in α1β3 GABAA receptors with lower potency and efficacy than ALLO, PREG or ent-PREG. The small PAM effect of ent-ALLO was prevented by the α1(Q242L) mutation in the intersubunit neurosteroid binding site between the β3 and α1 subunits. Consistent with this result, neurosteroid analogue photolabeling with mass spectrometric readout, showed that ent-ALLO binds weakly to the β3-α1 intersubunit binding site in comparison to ALLO, PREG and ent-PREG. Rigid body docking predicted that ent-ALLO binds in the intersubunit site with a preferred orientation 180° different than ALLO, PREG or ent-PREG, potentially explaining its weak binding and effect. Photolabeling studies did not identify differences between ALLO and ent-ALLO binding to the α1 or β3 intrasubunit binding sites that also mediate neurosteroid modulation of GABAA receptors. The results demonstrate that differential binding of ent-ALLO and ent-PREG to the β3-α1 intersubunit site accounts for the difference in enantioselectivity between ALLO and PREG. Full article
(This article belongs to the Special Issue GABA(A) Receptors: Structure and Function)
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16 pages, 2128 KiB  
Article
Activation of the Rat α1β2ε GABAA Receptor by Orthosteric and Allosteric Agonists
by Allison L. Germann, Ariel B. Burbridge, Spencer R. Pierce and Gustav Akk
Biomolecules 2022, 12(7), 868; https://doi.org/10.3390/biom12070868 - 21 Jun 2022
Cited by 2 | Viewed by 1497
Abstract
GABAA receptors are a major contributor to fast inhibitory neurotransmission in the brain. The receptors are activated upon binding the transmitter GABA or allosteric agonists including a number of GABAergic anesthetics and neurosteroids. Functional receptors can be formed by various combinations of [...] Read more.
GABAA receptors are a major contributor to fast inhibitory neurotransmission in the brain. The receptors are activated upon binding the transmitter GABA or allosteric agonists including a number of GABAergic anesthetics and neurosteroids. Functional receptors can be formed by various combinations of the nineteen GABAA subunits cloned to date. GABAA receptors containing the ε subunit exhibit a significant degree of constitutive activity and have been suggested to be unresponsive to allosteric agents. In this study, we have characterized the functional properties of the rat α1β2ε GABAA receptor. We confirm that the α1β2ε receptor exhibits a higher level of constitutive activity than typical of GABAA receptors and show that it is inefficaciously activated by the transmitter and the allosteric agonists propofol, pentobarbital, and allopregnanolone. Manipulations intended to alter ε subunit expression and receptor stoichiometry were largely without effect on receptor properties including sensitivity to GABA and allosteric agonists. Surprisingly, amino acid substitutions at the conserved 9’ and 6’ positions in the second transmembrane (TM2) domain in the ε subunit did not elicit the expected functional effects of increased constitutive activity and resistance to the channel blocker picrotoxin, respectively. We tested the accessibility of TM2 residues mutated to cysteine using the cysteine-modifying reagent 4-(hydroxymercuri)benzoic acid and found a unique pattern of water-accessible residues in the ε subunit. Full article
(This article belongs to the Special Issue GABA(A) Receptors: Structure and Function)
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Review

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14 pages, 1064 KiB  
Review
Benzodiazepine Modulation of GABAA Receptors: A Mechanistic Perspective
by Marcel P. Goldschen-Ohm
Biomolecules 2022, 12(12), 1784; https://doi.org/10.3390/biom12121784 - 30 Nov 2022
Cited by 12 | Viewed by 9001
Abstract
Benzodiazepines (BZDs) are a class of widely prescribed psychotropic drugs that target GABAA receptors (GABAARs) 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 [...] Read more.
Benzodiazepines (BZDs) are a class of widely prescribed psychotropic drugs that target GABAA receptors (GABAARs) 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 GABAA(α1)2(βX)2(γ2)1 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 GABAA(α1)2(βX)2(γ2)1 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. Full article
(This article belongs to the Special Issue GABA(A) Receptors: Structure and Function)
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