title: The human ether-a-go-go-related gene activator NS1643 enhances epilepsy-associated KCNQ channels.
abstract: Human ether-a-go-go-related gene (hERG) and KCNQ channels are two classes of voltage-gated potassium channels. Specific mutations have been identified that are causal for type II long QT (LQT2) syndrome, neonatal epilepsy, and benign familial neonatal convulsions. Increasing evidence from clinical studies suggests that LQT2 and epilepsy coexist in some patients. Therefore, an integral approach to investigating and treating the two diseases is likely more effective. In the current study, we found that NS1643 [1,3-bis-(2-hydroxy-5-trifluoromethyl-phenyl)-urea], a previously reported hERG activator, is also an activator of KCNQ channels. It potentiates the neuronal KCNQ2, KCNQ4, and KCNQ2/Q3 channels, but not the cardiac KCNQ1. The effects of NS1643 on the KCNQ2 channel include left shifting of voltage for reaching 50% of the maximum conductance and slowing of deactivation. Analysis of the dose-response curve of NS1643 revealed an EC50 value of 2.44 ± 0.25 μM. A hydrophobic phenylalanine (F137) located at the middle region of the voltage-sensing domain was identified as critical for NS1643 activity on KCNQ2. When testing NS1643 effects in rescuing LQT2 hERG mutants and the KCNQ2 BFNC mutants, we found it is particularly efficacious in some cases. Considering the substantial relationship between LQT2 and epilepsy, these findings reveal that NS1643 is a useful compound to elucidate the causal connection of LQT2 and epilepsy. More generally, this may provide a strategy in the development of therapeutics for LQT2 and epilepsy.
authors.affiliation: CAS Key Laboratory of Receptor Research (P.L., X.C., Y.Z., Z.G.), and State Key Laboratory of Drug Research (Q.Z., H.J., H.Y.), Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Li
authors.affiliation: CAS Key Laboratory of Receptor Research (P.L., X.C., Y.Z., Z.G.), and State Key Laboratory of Drug Research (Q.Z., H.J., H.Y.), Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Xueqin
authors.initials: X
authors.lastname: Chen
authors.affiliation: CAS Key Laboratory of Receptor Research (P.L., X.C., Y.Z., Z.G.), and State Key Laboratory of Drug Research (Q.Z., H.J., H.Y.), Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Qiansen
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: CAS Key Laboratory of Receptor Research (P.L., X.C., Y.Z., Z.G.), and State Key Laboratory of Drug Research (Q.Z., H.J., H.Y.), Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Yueming
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: CAS Key Laboratory of Receptor Research (P.L., X.C., Y.Z., Z.G.), and State Key Laboratory of Drug Research (Q.Z., H.J., H.Y.), Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
authors.affiliation: CAS Key Laboratory of Receptor Research (P.L., X.C., Y.Z., Z.G.), and State Key Laboratory of Drug Research (Q.Z., H.J., H.Y.), Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China zbgao@simm.ac.cn hyyang@simm.ac.cn.
authors.forename: Huaiyu
authors.initials: H
authors.lastname: Yang
authors.affiliation: CAS Key Laboratory of Receptor Research (P.L., X.C., Y.Z., Z.G.), and State Key Laboratory of Drug Research (Q.Z., H.J., H.Y.), Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China zbgao@simm.ac.cn hyyang@simm.ac.cn.
authors.forename: Zhaobing
authors.initials: Z
authors.lastname: Gao
mesh_terms: D000818:Animals; D016466:CHO Cells; D003408:Cresols / Q000378:metabolism* / Q000494:pharmacology*; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D004827:Epilepsy / Q000378:metabolism*; D051638:Ether-A-Go-Go Potassium Channels / Q000819:agonists / Q000378:metabolism*; D006801:Humans; D051658:KCNQ2 Potassium Channel / Q000819:agonists / Q000378:metabolism*; D010671:Phenylurea Compounds / Q000378:metabolism* / Q000494:pharmacology*; D017433:Protein Structure, Secondary
chemical_list: D003408:Cresols; D051638:Ether-A-Go-Go Potassium Channels; D051658:KCNQ2 Potassium Channel; C496914:KCNQ2 protein, human; D010671:Phenylurea Compounds; C507624:1,3-bis(2-hydroxy-5-trifluoromethylphenyl)urea