Looking for Novelty in an “Old” Receptor: Recent Advances Toward Our Understanding of GABAARs and Their Implications in Receptor Pharmacology

Abstract

Diverse populations of GABAA receptors (GABAARs) throughout the brain mediate fast inhibitory transmission and are modulated by various endogenous ligands and therapeutic drugs. Deficits in GABAAR signaling underlie the pathophysiology behind neurological and neuropsychiatric disorders such as epilepsy, anxiety, and depression. Pharmacological intervention for these disorders relies on several drug classes that target GABAARs, such as benzodiazepines and more recently neurosteroids. It has been widely demonstrated that subunit composition and receptor stoichiometry impact the biophysical and pharmacological properties of GABAARs. However, current GABAAR-targeting drugs have limited subunit selectivity and produce their therapeutic effects concomitantly with undesired side effects. Therefore, there is still a need to develop more selective GABAAR pharmaceuticals, as well as evaluate the potential for developing next-generation drugs that can target accessory proteins associated with native GABAARs. In this review, we briefly discuss the effects of benzodiazepines and neurosteroids on GABAARs, their use as therapeutics, and some of the pitfalls associated with their adverse side effects. We also discuss recent advances toward understanding the structure, function, and pharmacology of GABAARs with a focus on benzodiazepines and neurosteroids, as well as newly identified transmembrane proteins that modulate GABAARs.

An Electrophysiological and Pharmacological Study of the Properties of Human iPSC-Derived Neurons for Drug Discovery

“…Sensitivity to the benzodiazepines, chlordiazepoxide and diazepam, is conferred by the presence of the γ2 receptor subunit in the GABA A receptor complex [32,33] whilst sensitivity to the NSAID, mefenamic acid is conferred by the presence of the β2/β3 subunits in the receptor complex [4,34]. We can therefore deduce from our electrophysiological data that the GABA A receptor isoforms expressed by iCells are likely composed of αxβ2/3γ2 subunits (where x is one of several possible α subunits) to enable the rich and complex pharmacological responses observed to these clinically important agents and consistent with native GABA A receptor pharmacology [35]. Measurements of mRNA expression levels of GABA A receptor subunits in iCell neurons are also entirely consistent with our patch-clamp data [7,11].…”

Targeting Endocannabinoid Signaling in the Lateral Habenula as an Intervention to Prevent Mental Illnesses Following Early Life Stress: A Perspective

“…In fact, many receptors can exist in nature as receptor complexes where accessory proteins or auxiliary subunits can impact receptor trafficking, kinetics, and pharmacology (Maher et al, 2017). Already, these accessory proteins have been identified for VGCCs (Campiglio and Flucher, 2015), AMPARs (Kamalova and Nakagawa, 2021), nAChRs (Boulin et al, 2012), and most recently GABA A Rs (Castellano et al, 2020;Han et al, 2020). Indeed, targeting of auxiliary subunits has already succeeded with gabapentin being used for the treatment of epilepsy and pain.…”

Neuroplastin in Neuropsychiatric Diseases

“…The dysfunction of GABAergic transmission contributes to several neurological conditions, such as depression, anxiety, epilepsy (for a review, see: [78]), SZ [79], and ASD [80,81]. Based on the considerable combinatorial possibilities, a novel and more specific pharmacological intervention has been proposed as a potential advancement for clinical treatment over the use of nonselective GABA A receptor agonists (for a review, see: [78,82]. Furthermore, accessory molecules that interact with GABA A receptors may be new potential targets.…”