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Ligand-gated ion channels in genetic disorders and the question of efficacy.
The International Journal of Biochemistry & Cell Biology ( IF 4 ) Pub Date : 2020-07-15 , DOI: 10.1016/j.biocel.2020.105806
Nathan L Absalom 1 , Vivian W Liao 1 , Mary Chebib 1
Affiliation  

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.



中文翻译:

遗传疾病中的配体门离子通道和功效问题。

全基因组测序已在与遗传疾病相关的离子通道中发现了大量个体变异。长期以来,已知包括甘氨酸,γ-氨基丁酸A型和烟碱型乙酰胆碱受体在内的配体门离子通道具有与高度上垂和癫痫病相关的遗传变异。在这些情况中的某些情况下,错义变体增强或削弱了受体将配体结合转变为通道开放的内在能力,或增强了受体激活的功效。我们回顾了当前对配体门控离子通道如何被激活以及定义激动剂功效的特性的理解,以及如何通过致病变体改变这些特性。另外,我们考虑了定义受体药物调制的机制,并考虑了遗传变异中的差异。对于了解配体门控离子通道中遗传变异患者的有效治疗方法,这一基础知识可能至关重要。

更新日期:2020-07-15
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