Structural pharmacology of GABAА receptors

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Abstract

Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the mammalian central nervous system (CNS), activating the inotropic type A receptors (GABAА receptors) to provide fast inhibition. GABAА receptors are the main target for various groups of drugs that are widely used in the treatment of CNS disorders.

This review examines the relationship between the physiological effects of GABAА receptor activation and modulation by various substances (including medicinal compounds), the receptor's structure, and the interaction of these substances with specific modulatory sites. Recent advances in cryogenic electron microscopy have led to fundamental improvements in understanding the detailed organization and function of GABAА receptors. This review is based on both the latest structural data obtained from cryogenic electron microscopy and the results of biochemistry and electrophysiology studies, as well as molecular modelling.

About the authors

Alexey V. Rossokhin

Research Center of Neurology

Author for correspondence.
Email: alrossokhin@yahoo.com
ORCID iD: 0000-0001-7024-7461

Cand. Sci. (Phys.-Math.), leading researcher, Laboratory of functional synaptology

Russian Federation, Moscow

Irina N. Sharonova

Research Center of Neurology

Email: alrossokhin@yahoo.com
ORCID iD: 0000-0001-9955-1870

D. Sci. (Biol.), leading researcher, Laboratory of functional synaptology

Russian Federation, Moscow

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Supplementary files

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2. Fig. 1. GABAA receptor architecture. A — view parallel to the membrane plane towards 2:2:1 α1β2γ2 receptor (6X3Z). The subunits are marked with colours and letters (αl is blue- feen, β2 is orange, and y2 is magenta). B — structure of a single subunit. N and С — amino acid chain terminals, ECD С-loop and cys-loop, М1-М4 - transmembrane helices, М2-М3 — TMD loop. C — view from the intracellular space towards the ECD. Intersubunit interfaces are marked with +/-. The electronic densities of GABA and diazepam in β+/α- and α+/γ- interfaces are shown. D — view from the extra space towards the TMD. Transmembrane intersubunit interfaces to which positive allosteric modulators bind are shown: β+/α- — general anaesthetics (etomidate (ETM) and propofol (PPF)), benzodiazepines (diazepam (DZP)), neuroactive steroids (allopregnanolone (ALP)); α+/β- barbiturates (phenobarbital (PBT)); β-/γ+ — barbiturates (PBT), benzodiazepines (DZP).

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3. Fig. 2. Orthosteric site in the ECD with bound GABA (А) and the competitive antagonist bicuculline (B). Side chains of the residues, which play the biggest role in ligand interaction, are demonstrated. Hydrogen bonds and polar contacts are shown as red dashed lines. Only the polar hydrogen atoms are shown. C — overlay of the two cryo-EM structures: GABAA receptor with bound GABA (PDB ID 6X3Z) and with bicuculline (PDB ID 6X3S). The TMD and some structural elements of the ECD αl and β2 subunits are not shown for clarity purposes. The subunit colours correspond to those in Fig. 1, but a lighter shade is used for the 6X3Z structure in the C fragment. The arrow indicates the change in the C-loop conformation

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4. Fig. 3. BZD binding site in the ECD α+/γ- interface. A, B — cryo-EM structures with bound DZP (6X3X) and flumazenil (6X3U). C, D — structural models of zolpidem and the thiazole analogue imidaz- opyridine (compound 37) binding in the ECD α+/γ- interface. Labels in A-D correspond to the terms in Fig. 1 and 2.

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5. Fig. 4. Alignment of the amino acid sequences of the М1-М3 segments in the various subunits of the GABAA, receptor and glycine receptor. The sequences are taken from the UniProt database with the identification numbers GABAA_αl P14867, GABAA_β2 P47870, GABAA_β3 P28472, GABAA_γ2 P18507, GlyR_α1 093430 and GlyR_α3 075311. The alignment was performed relative to the highly-conserved Arg residues in the cytoplasmic part of the M2 helices (0'). The numbers on the right indicate the number of the last residue in the sequence.

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6. Fig. 5. Intravenous anaesthetic binding in the TMD. A, B — ETM (6X3V) and PPF (6X3T) in the β+/α- interface. C — binding sites of PBT (6X3V) in the α+/β- (top) and the β-/γ+ (bottom) interfaces. D — binding sites of DZP (6X3X) in the β+/α- (top) and the β-/γ+ (bottom) interfaces. A-D show only fragments of the М1-М3 helices. Labels in A-D correspond to the terms in Fig. 1 and 2.

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7. Fig.6. Binding of the neuroactive steroid ALP in the β+/α–- transmembrane intersubunit interface. A — a full size β+/α– intersubunit interface of an open α1β2γ2- GABAa receptor model, based on homology with the αl glycine receptor (3JAE). The ALP binding site and the electron densities corresponding to GABA (ECD) and ETM (TMD) are shown. B — ALP binding site, magnified. Fragments of TMD М1-М3 helices are shown. Labels in A and B correspond to the terms in Fig. 1 and 2.

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Copyright (c) 2021 Rossokhin A.V., Sharonova I.N.

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