Looking for Novelty in an “Old” Receptor: Recent Advances Toward Our Understanding of GABA(A)Rs and Their Implications in Receptor Pharmacology

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