TY - JOUR TI - Distinctive mechanisms of epilepsy-causing mutants discovered by measuring S4 movement in KCNQ2 channels AU - Edmond, Michaela A AU - Hinojo-Perez, Andy AU - Wu, Xiaoan AU - Perez Rodriguez, Marta E AU - Barro-Soria, Rene A2 - Sack, Jon T A2 - Swartz, Kenton J A2 - Sack, Jon T VL - 11 PY - 2022 DA - 2022/06/01 SP - e77030 C1 - eLife 2022;11:e77030 DO - 10.7554/eLife.77030 UR - https://doi.org/10.7554/eLife.77030 AB - 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. KW - KCNQ2 KW - Kv7.2 KW - epilepsy KW - voltage clamp fluorometry KW - cysteine accessibility KW - KCNQ gating scheme JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -