AUTHOR=Castellano David , Shepard Ryan David , Lu Wei 

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

JOURNAL=Frontiers in Neuroscience

VOLUME=14

YEAR=2021

URL=https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2020.616298

DOI=10.3389/fnins.2020.616298

ISSN=1662-453X

ABSTRACT=<p>Diverse populations of GABA<sub>A</sub> receptors (GABA<sub>A</sub>Rs) throughout the brain mediate fast inhibitory transmission and are modulated by various endogenous ligands and therapeutic drugs. Deficits in GABA<sub>A</sub>R 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 GABA<sub>A</sub>Rs, 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 GABA<sub>A</sub>Rs. However, current GABA<sub>A</sub>R-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 GABA<sub>A</sub>R pharmaceuticals, as well as evaluate the potential for developing next-generation drugs that can target accessory proteins associated with native GABA<sub>A</sub>Rs. In this review, we briefly discuss the effects of benzodiazepines and neurosteroids on GABA<sub>A</sub>Rs, 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 GABA<sub>A</sub>Rs with a focus on benzodiazepines and neurosteroids, as well as newly identified transmembrane proteins that modulate GABA<sub>A</sub>Rs.</p>