Distinctive mechanisms of epilepsy-causing mutants discovered by measuring S4 movement in KCNQ2 channels
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TL;DR: In this paper , the parameters of voltage sensor movements in wt-KCNQ2 and channels bearing epilepsy-associated mutations using cysteine accessibility and voltage clamp fluorometry (VCF) were defined.
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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.
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Citations
Genetic Background of Epilepsy and Antiepileptic Treatments
Kinga K. Borowicz-Reutt,Julia Czernia,Marlena Krawczyk +2 more
TL;DR: Advanced identification of the gene mutations causing epilepsy syndromes is expected to translate into faster diagnosis and more effective treatment of these conditions, which facilitates more favorable selection of drugs for anticonvulsant therapy.
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Electro-mechanical coupling of KCNQ channels is a target of epilepsy-associated mutations and retigabine
Nien-Du Yang,Richard Kanyo,Lu Zhao,Jingru Li,Po Wei Kang,Alex K. Dou,Kelli McFarland White,Jingyi Shi,Jeanne M. Nerbonne,Harley T. Kurata,Jianmin Cui +10 more
TL;DR: It is shown thatKCNQ2 and KCNQ3 feature only a single conductive AO state but with a conserved mechanism for the electro-mechanical (E-M) coupling between voltage sensor activation and pore opening.
Voltage-gated ion channels in epilepsies: circuit dysfunctions and treatments
Dominique Debanne,Konstantina Mylonaki,Maria Laura Musella,Michaël Russier +3 more
TL;DR: Voltage-gated ion channels play a critical role in regulating neuronal excitation and synaptic transmission in epilepsies, with genetic alterations and pharmacological targeting of these channels offering potential therapeutic avenues for epilepsy treatment and management.
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Lipophilic compounds restore function to neurodevelopmental-associated KCNQ3 mutations
Michaela Edmond,Andy Hinojo-Perez,Mekedlawit Efrem,Yi-Chun Lin,Iqra Shams,Sébastien Hayoz,Alicia de la Cruz,Marta E Perez Rodriguez,Maykelis Diaz-Solares,Derek M. Dykxhoorn,Yun Luo,René Barro-Soria +11 more
TL;DR: Lipophilic compounds restore function to KCNQ3 mutations, a common cause of neurodevelopmental disorders, by rescuing neuronal hyperexcitability and improving cellular excitability, offering a potential therapeutic strategy for KCNQ3-related disorders.
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The Voltage-Sensor S4 Rises to the Occasion in KCNQ2 Channel Activation
TL;DR: In this article , the authors defined the parameters of voltage sensor movements in wt-KCNQ2 and channels bearing epilepsy-associated mutations using cysteine accessibility and voltage clamp fluorometry (VCF).
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TL;DR: Findings show that movement of the NH2- terminal half but not the CO2H-terminal end of the S4 segment underlies gating charge, and that this portion of theS4 segment appears to move across the entire transmembrane voltage difference in association with channel activation.
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Voltage-Sensing Residues in the S2 and S4 Segments of the Shaker K+ Channel
TL;DR: The results indicate that conserved charged amino acids in putative transmembrane segments S2, S3, and S4 contribute to the gating charge of the channel and are a major component of the voltage sensor.
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Pathways modulating neural KCNQ/M (Kv7) potassium channels
Patrick Delmas,Daniel A Brown +1 more
TL;DR: Recent developments that have begun to clarify the link between the receptors and the channels are summarized and their implications for physiology and medicine are discussed.
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Direct Physical Measure of Conformational Rearrangement Underlying Potassium Channel Gating
TL;DR: During channel activation, a stretch of at least seven amino acids of the putative transmembrane segment S4 moved from a buried position into the extracellular environment, providing physical evidence in support of the hypothesis that S4 is the voltage sensor of voltage-gated ion channels.
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Transmembrane Movement of the Shaker K+ Channel S4
TL;DR: These results demonstrate that the putative voltage-sensing charges of S4 actually reside in the membrane and that they move outward when channels open, and consider constraints placed on channel structure.
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