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Review
. 2017 Jul;174(13):1881-1894.
doi: 10.1111/bph.13768. Epub 2017 Apr 12.

GABA-ρ receptors: distinctive functions and molecular pharmacology

Moawiah M Naffaa  1 , Sandy Hung  1 , Mary Chebib  1 , Graham A R Johnston  2 , Jane R Hanrahan  1
Affiliations
Review

GABA-ρ receptors: distinctive functions and molecular pharmacology

Moawiah M Naffaa et al. Br J Pharmacol. 2017 Jul.

Abstract

The homomeric GABA-ρ ligand-gated ion channels (also known as GABAC or GABAA -ρ receptors) are similar to heteromeric GABAA receptors in structure, function and mechanism of action. However, their distinctive pharmacological properties and distribution make them of special interest. This review focuses on GABA-ρ ion channel structure, ligand selectivity toward ρ receptors over heteromeric GABAA receptor sub-types and selectivity between different homomeric ρ sub-type receptors. Several GABA analogues show selectivity at homomeric GABA-ρ receptors over heteromeric GABAA receptors. More recently, some synthetic ligands have been found to show selectivity at receptors formed from one ρ subtype over others. The unique pharmacological profiles of these agents are discussed in this review. The classical binding site of GABA within the orthosteric site of GABA-ρ homomeric receptors is discussed in detail regarding the loops and residues that constitute the binding site. The ligand-residue interactions in this classical binding and those of mutant receptors are discussed. The structure and conformations of GABA are discussed in regard to its flexibility and molecular properties. Although the binding mode of GABA is difficult to predict, several interactions between GABA and the receptor assist in predicting its potential conformation and mode of action. The structure-activity relationships of GABA and structurally key ligands at ρ receptors are described and discussed.

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Figures

Figure 1
Figure 1
Pentameric ligand‐gated ion channel receptor of GABA‐ρ homology model based on GluCl structure prepared has been previously described (Naffaa et al., 2015). A single ion channel showing the main domains with five identical subunits, coloured differently to show the intersubunit interfaces located between the principal (+) and complementary (−) sides. (A) Bottom view and (B) side view. As the structure of the intracellular domain has not yet been determined by crystallography, it is not included.
Figure 2
Figure 2
Chemical structures of ligands that selectively distinguish GABA‐ρ1 receptors from GABAA receptors.
Figure 3
Figure 3
The amino acid sequence alignment of GABA‐ρ1, GABA‐ρ2 and GABA‐ρ3 subunits. Alignments were prepared as previously described (Naffaa et al., 2015). The amino acid sequence of various human GABA‐ρ receptors was obtained from the Universal Protein Resources (http://www.uniprot.org/) (UniProt Consortium, 2013). The UniProt IDs for GABA‐ρ1, GABA‐ρ2 and GABA‐ρ3 subunits are P24046, P28476 and A8MPY1 respectively.
Figure 4
Figure 4
The amino acids sequence alignment of GluCl, GABA α1, GABAγ2, GABA ρ1, GABA β3 and GABA β2 subunits. The different shades of blue highlights show the conserved amino acids between the template ‘GluCl’ and the studied GABA subunits in this review. Dark blue indicates that the residue is conserved between all or most of the subunits, while light blue indicates that residue is conserved or related to another residue in two or three subunits only. Alignments were prepared as previously described (Naffaa et al., 2015). The amino acid sequence of human GABA and GluCl subunits was obtained from the Universal Protein Resources (http://www.uniprot.org/) (UniProt Consortium, 2013) and Protein Data Bank (PDB). UniProtKT ID for GABA α1, GABAγ2, GABAρ1 and GABA β2 subunits are P14867, P18507, P24046 and P47870–1 respectively. PDB ID for GluCl and GABA β3 are 3RIF and 4COF respectively.
Figure 5
Figure 5
Molecular basis of GABA bound in the orthosteric binding site of GABA ρ1 homology model based on GluCl. (A) GABA bound GABA‐ρ1 homology model based on GluCl, showing loops A–G (labelled in red), and H‐bond interactions formed between GABA and Thr244 and Ser168, and salt bridges with Arg104 and Glu196. Arg158 and Arg170 are two important residues for protein stability either by forming interaction within the same subunit or between neighbouring subunits. (B) GABA and aromatic residues (Tyr102, Tyr198, Tyr241 and Tyr247) forming the aromatic box that stabilizes GABA in the binding site during the channel gating. The Phe138 residue may form important interactions as it has a benzene ring system that partially oriented to both the GABA binding site and the adjacent subunit.
Figure 6
Figure 6
(A) Chemical structure of picrotoxinin. (B) The amino acids sequence alignment of the second TM domain of human GABA ρ1 and ρ2 subunits against the GABA rat ρ1 subunit.
Figure 7
Figure 7
Chemical structures of ligands demonstrate subunit selectivity between homomeric receptors composed of different GABA ρ subunits.
Figure 8
Figure 8
Chemical structures of ligands used to study structure activity relationships at GABA‐ρ receptors.
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