Expert view: Unravelling the complexities of GABAA subunit selectivity in drug discovery

GABAA receptors represent a large and complicated family of ion channels that consist of at least 16 subunits (α1-6, β1-3, γ1-3, δ, ε, π, θ) that have been shown to be vital for the normal functioning of the brain. These inhibitory ligand-gated channels have been shown to beimportant in sedation, muscle relaxation and anaesthesia as well as being important drug targets for the treatment of neuronal disorders such asepilepsy and anxiety.

However, the physiological and pharmacological complexity of the GABAA receptors should not be underestimated. In the past few decades, thanks to the contribution of genetics, in-vivo modelling and in-vitro electrophysiology, a more complicated view of the physiological and pharmacological functions of the GABAA receptors has emerged in which each single subunit (e.g. alpha, beta and gamma), their relationship within the pentameric structure (eg, 2 α, 2 β, 1 γ) and their relative distribution in the body, may mediate a specific physiological function.

The advent of 384 and 768‑well automated electrophysiology platforms has significantly increased the possibility to run high‑throughput screening campaigns against a range of GABAA subunit combinations, generating a wealth of high‑quality electrophysiology data and guiding researchers on compound potency and subtype selectivity. In combination with robust, high‑quality cell line reagents, we have the potential to speed up the search for lead candidates in the GABAA receptor drug discovery process, and for the first time offer the possibility to quickly assess the molecular mechanisms of these potential drug candidates. In the future, the hope is to achieve more selective GABAA receptor‑targeted drugs in order to improve their efficacy, safety and tolerability for a range of therapeutic purposes.