Pharmacological Effect of GABA Analogues on GABA-ρ2 Receptors and Their Subtype Selectivity

GABAρ receptors are distinctive GABAergic receptors from other ionotropic GABA(A) and metabotropic GABA(B) receptors in their pharmacological, biochemical, and electrophysiological properties. Although GABA-ρ1 receptors are the most studied in this subfamily, GABA-ρ2 receptors are widely distributed in the brain and are considered a potential target for treating neurological disorders such as stroke. The structure of GABA-ρ2 receptors and their pharmacological features are poorly studied. We generated the first homology model of GABA-ρ2 channel, which predicts similar major interactions of GABA with the binding-site residues in GABA-ρ1 and GABA-ρ2 channels. We also investigated the pharmacological properties of several GABA analogues on the activity of GABA-ρ2 receptors. In comparison to their pharmacological effect on GABA-ρ1 receptors, the activation effect of these ligands and their potentiation/inhibition impact on GABA response have interestingly shown inter-selectivity between the two GABA-ρ receptors. Our results suggest that several GABA analogues can be used as research tools to study the distinctive physiology of GABA-ρ1 and GABA-ρ2 receptors. Furthermore, their partial agonist effect may hold promise for the future discovery of selective modulatory agents on GABA(A) receptors.