title: Epilepsy-Related Slack Channel Mutants Lead to Channel Over-Activity by Two Different Mechanisms.
abstract: Twelve sodium-activated potassium channel (KCNT1, Slack) genetic mutants have been identified from severe early-onset epilepsy patients. The changes in biophysical properties of these mutants and the underlying mechanisms causing disease remain elusive. Here, we report that seven of the 12 mutations increase, whereas one mutation decreases, the channel's sodium sensitivity. Two of the mutants exhibit channel over-activity only when the intracellular Na(+) ([Na(+)]i) concentration is ∼80 mM. In contrast, single-channel data reveal that all 12 mutants increase the maximal open probability (Po). We conclude that these mutant channels lead to channel over-activity predominantly by increasing the ability of sodium binding to activate the channel, which is indicated by its maximal Po. The sodium sensitivity of these epilepsy causing mutants probably determines the [Na(+)]i concentration at which these mutants exert their pathological effects.
authors.affiliation: Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical College, Xuzhou, Jiangsu Province 221004, China; Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical College, Xuzhou, Jiangsu Province 221004, China.
authors.forename: Qiong-Yao
authors.initials: QY
authors.lastname: Tang
authors.affiliation: Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical College, Xuzhou, Jiangsu Province 221004, China; Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical College, Xuzhou, Jiangsu Province 221004, China.
authors.forename: Fei-Fei
authors.initials: FF
authors.lastname: Zhang
authors.affiliation: Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical College, Xuzhou, Jiangsu Province 221004, China; Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical College, Xuzhou, Jiangsu Province 221004, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Xu
authors.affiliation: School of Anesthesiology, Xuzhou Medical College, Xuzhou, Jiangsu Province 221004, China.
authors.forename: Ran
authors.initials: R
authors.lastname: Wang
authors.affiliation: School of Anesthesiology, Xuzhou Medical College, Xuzhou, Jiangsu Province 221004, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Physiology and Biophysics, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Diomedes E
authors.initials: DE
authors.lastname: Logothetis
authors.affiliation: Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical College, Xuzhou, Jiangsu Province 221004, China; Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical College, Xuzhou, Jiangsu Province 221004, China. Electronic address: zhangzhe70@xzmc.edu.cn.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Zhang
mesh_terms: D000818:Animals; D004827:Epilepsy / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D017136:Ion Transport / Q000235:genetics; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D015221:Potassium Channels / Q000235:genetics / Q000378:metabolism*; D000081033:Potassium Channels, Sodium-Activated; D012964:Sodium / Q000378:metabolism*; D014982:Xenopus laevis
chemical_list: C585122:KCNT1 protein, human; D009419:Nerve Tissue Proteins; D015221:Potassium Channels; D000081033:Potassium Channels, Sodium-Activated; D012964:Sodium