GABA‐ρ receptors: distinctive functions and molecular pharmacology

Abstract

The homomeric GABA-ρ ligand-gated ion channels (also known as GABA or GABA -ρ receptors) are similar to heteromeric GABA 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 GABA receptor sub-types and selectivity between different homomeric ρ sub-type receptors. Several GABA analogues show selectivity at homomeric GABA-ρ receptors over heteromeric GABA 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.

International Union of Basic and Clinical Pharmacology. CVI: GABAAReceptor Subtype- and Function-selective Ligands: Key Issues in Translation to Humans

“…GABA A Receptors r-Containing receptors form homo-oligomers or heterooligomers with other r subunits or possibly even with some other GABA A receptor or glycine receptor subunits (Qian and Ripps, 1999;Pan et al, 2000;Hartmann et al, 2004;Milligan et al, 2004;Frazao et al, 2007). Originally, r-containing receptors were named GABA C receptors because of some differences in their pharmacology compared with GABA A receptors (Chebib, 2004;Martínez-Delgado et al, 2010;Ng et al, 2011;Naffaa et al, 2017). Due to the sequence homology of r-subunits with other GABA A receptor subunits as well as the structural homology of r-containing receptors with abg GABA A receptors, the International Union of Pharmacology nomenclature commission decided that r-containing receptors belong to the GABA A receptor family and should be classified as such (Barnard et al, 1998;Olsen and Sieghart, 2008).…”

GABA is a modulator, rather than a classical transmitter, in the medial nucleus of the trapezoid body–lateral superior olive sound localization circuit

“…Notably, our RNA sequencing analysis identified transcripts for the ρ2 subunit, albeit at a low level (position 13). ρ subunits assemble into ionotropic homomeric receptors originally named GABA C Rs, but after reclassification they are seen as a specialized set of GABA A Rs often referred to as GABA A -ρ receptors (Naffaa et al 2017). GABA A -ρ receptors are insensitive to GABA A R modulators like benzodiazepines, barbiturates and steroids (Bormann & Feigenspan, 1995;Bormann, 2000).…”

“…Metabotropic glycine receptors have not been identified in mammals (Tritsch et al 2016). By contrast, GABAergic signalling appears to be much more complex, because it is mediated through heteropentameric ionotropic receptors (GABA A/C Rs) composed of eight classes of subunits (α, β, γ, δ, ε, θ, π, ρ) with a total of 19 identified isoforms (Rudolph & Möhler, 2014;Smart, 2015;Naffaa et al 2017). Moreover, GABA can act on G protein-coupled receptors (GABA B Rs), which are also very heterogeneous, displaying pronounced diversity in subcellular location, functional properties and cellular signalling (Brenowitz et al 1998;Xu et al 2014;Schwenk et al 2016).…”

Mutation of the inhibitory ethanol site in GABA A ρ1 receptors promotes tolerance to ethanol-induced motor incoordination

“…In contrast to classical heteromeric GABA A receptors, homomeric ρ1 receptors are inhibited by ethanol (Mihic and Harris, 1996) and have other distinctive functions (Naffaa et al, 2017). The ρ1 subunit was shown to have a specific inhibitory site for ethanol (Borghese et al, 2016).…”