Ligand-gated ion channels in genetic disorders and the question of efficacy.

Abstract Whole-genome sequencing has unearthed a substantial number of individual variants in ion channels associated with genetic disorders. Ligand-gated ion channels, including glycine, γ-aminobutyric acid type A and nicotinic acetylcholine receptors, have long been known to harbour genetic variants associated with hyperekplexia and different forms of epilepsy. In some of these cases, missense variants enhance or impair the intrinsic ability of the receptor to convert ligand binding to channel opening, or the efficacy of receptor activation. We review the current understanding of how ligand-gated ion channels are activated and the properties that define the efficacy of an agonist, and how these properties can be altered by disease-causing variants. Additionally, we consider the mechanisms defining drug modulation of receptors and consider how this may differ in genetic variants. This fundamental knowledge is likely to be essential in understanding how effective treatments will be for patients with genetic variants in ligand-gated ion channels.