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

Abstract

GABAϱ receptors are distinctive GABAergic receptors from other ionotropic GABAA and metabotropic GABAB 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 GABAA receptors.

GABA, glucose and insulin orchestrate CD4+T cells effector functions

“…4a, b, c), in activated CD4 + T cells treated with or without insulin. TACA and TPMPA are more selective for π-containing GABA A R 25,28,29 . Ca 2+ release-activated Ca 2+ (CRAC) channels mediate store operated calcium entry (SOCE) in T cells that is central to the Ca 2+ homeostasis and cytoplasmic Ca 2+ levels 27 .…”

“…GABA A Rs are widespread in the brain and are present in many other tissues 38 but GABA A Rs containing GABRR2 (ρ2 subunit) are rare outside the immune system, with the exception of the retina 39 . GABA A R-ρ2 might be a valuable and a rather specific drug target 28 . SGLT2 inhibitors such as empagliflozin, are already in clinical use 40 and might be considered to cover new areas of application.…”

GABA-mediated inhibition of human CD4+ T cell functions is enhanced by insulin but impaired by high glucose levels

“… 47 , 49 The GABA A R-ρ2 are abundantly expressed in the CD4 + T cells and are upregulated by insulin, suggesting they might be a valuable and rather specific drug target. 47 , 50 Insulin shifted the GABA A R signalling by making it supersensitive to GABA, enhancing the GABA-switch, and consequently augmented the Ca 2+ entry through CRAC channels, an elegant way of modulating intracellular Ca 2+ levels and intracellular processes affecting T cell functions.…”

Milestone review: GABA, from chemistry, conformations, ionotropic receptors, modulators, epilepsy, flavonoids, and stress to neuro‐nutraceuticals

“…Significant were the improvements in synthetic organic chemistry and the use of functional human receptors expressed in oocytes (Miledi et al., 2002). Extensive molecular modelling has been carried out distinguishing ρ1 and ρ2 GABA C receptors suggesting several GABA analogues which can be used as partial agonists to discover selective modulatory agents for these receptors (Naffaa et al., 2022).…”