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XB-ART-59143
Elife January 1, 2022; 11
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Distinctive mechanisms of epilepsy-causing mutants discovered by measuring S4 movement in KCNQ2 channels.

Edmond MA , Hinojo-Perez A , Wu X , Perez Rodriguez ME , Barro-Soria R .


Abstract
Neuronal KCNQ channels mediate the M-current, a key regulator of membrane excitability in the central and peripheral nervous systems. Mutations in KCNQ2 channels cause severe neurodevelopmental disorders, including epileptic encephalopathies. However, the impact that different mutations have on channel function remains poorly defined, largely because of our limited understanding of the voltage-sensing mechanisms that trigger channel gating. Here, we define the parameters of voltage sensor movements in wt-KCNQ2 and channels bearing epilepsy-associated mutations using cysteine accessibility and voltage clamp fluorometry (VCF). Cysteine modification reveals that a stretch of eight to nine amino acids in the S4 becomes exposed upon voltage sensing domain activation of KCNQ2 channels. VCF shows that the voltage dependence and the time course of S4 movement and channel opening/closing closely correlate. VCF reveals different mechanisms by which different epilepsy-associated mutations affect KCNQ2 channel voltage-dependent gating. This study provides insight into KCNQ2 channel function, which will aid in uncovering the mechanisms underlying channelopathies.

PubMed ID: 35642783
Article link: Elife
Grant support: [+]

Species referenced: Xenopus laevis
Genes referenced: kcnq1 kcnq2 kcnq3 mapt

Disease Ontology terms: autism spectrum disorder [+]

Article Images: [+] show captions
References [+] :
Abbott, Ion channels under the sun. 2014, Pubmed