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

David Castellano,Wei Lu,Ryan David Shepard

doi:10.3389/fnins.2020.616298

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.

Highlights

Efforts aimed at uncovering mechanisms driving inhibitory transmission have contributed to our understanding of nervous system function, but have led to the development of several drugs used in the treatment of neurological and psychiatric disorders
Our review will briefly focus on the role of GABAA receptors (GABAARs) dysfunction in epilepsy, anxiety, and postpartum depression (PPD) as GABAAR-based pharmacotherapy is primarily employed as a treatment strategy in these conditions
Characterization and investigation of the various binding sites on GABAARs have provided invaluable data for the development of pharmaceuticals that are used to treat a wide variety of neurological conditions and psychiatric disorders

Summary

INTRODUCTION

Efforts aimed at uncovering mechanisms driving inhibitory transmission have contributed to our understanding of nervous system function, but have led to the development of several drugs used in the treatment of neurological and psychiatric disorders. Several therapeutic drug classes, including barbiturates, benzodiazepines, general anesthetics, and neurosteroids, target GABAARs at distinct allosteric binding sites and are commonly used to treat these disorders (Olsen and Sieghart, 2009; Olsen, 2018) They are widely employed for their sedative-hypnotic, anxiolytic, anticonvulsant, and/or muscle relaxant properties (Sieghart and Savic, 2018), adverse consequences such as drug dependence and withdrawal set limitations to their long-term use (Lalive et al, 2011; Tan et al, 2011; Balon and Starcevic, 2020). Our review will briefly focus on the role of GABAAR dysfunction in epilepsy, anxiety, and postpartum depression (PPD) as GABAAR-based pharmacotherapy is primarily employed as a treatment strategy in these conditions Due to their widespread use in these disorders, an update on GABAAR function and pharmacology with respect to benzodiazepines and neurosteroids will be given. We highlight potential opportunities in GABAAR pharmacology development as a result of these advancements

A BRIEF HISTORY ON GABAARs AS PROLIFIC DRUG TARGETS AND THEIR THERAPEUTIC USAGE

SUMMARY AND FUTURE OUTLOOK