Looking for Novelty in an “Old” Receptor: Recent Advances Toward Our Understanding of GABAARs and Their Implications in Receptor Pharmacology
David Castellano, Ryan D. Shepard, Wei Lü
Abstract
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.