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Research ArticleNeuropharmacology

The Human Ether-A-Go-Go–Related Gene Activator NS1643 Enhances Epilepsy-Associated KCNQ Channels

Ping Li, Xueqin Chen, Qiansen Zhang, Yueming Zheng, Hualiang Jiang, Huaiyu Yang and Zhaobing Gao
Journal of Pharmacology and Experimental Therapeutics December 2014, 351 (3) 596-604; DOI: https://doi.org/10.1124/jpet.114.217703
Ping Li
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
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Xueqin Chen
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
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Qiansen Zhang
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
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Yueming Zheng
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
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Hualiang Jiang
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
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Huaiyu Yang
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
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Zhaobing Gao
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
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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.

Footnotes

    • Received June 18, 2014.
    • Accepted September 16, 2014.
  • This work received supported by the State Key Program of Basic Research of China [Grant 2013CB910604]; the National Science and Technology Major Project on “Key New Drug Creation and Manufacturing Program” [Grant 2013ZX09103001-016]; the National Natural Science Foundation of China Grant for Excellent Key Laboratory [Grant 81123004]; the National Natural Science Foundation of China [Grants 61327014, 61175103, and 81173027]; Shanghai Municipal Science and Technology Commission [Grant 13JC1406700]; and the External Cooperation Program of BIC, Chinese Academy of Sciences [Grant 1536631KYSB20130003].

  • dx.doi.org/10.1124/jpet.114.217703.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 351 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 351, Issue 3
1 Dec 2014
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Research ArticleNeuropharmacology

NS1643 Rescues Both LQT2 and Epileptic Phenotypes

Ping Li, Xueqin Chen, Qiansen Zhang, Yueming Zheng, Hualiang Jiang, Huaiyu Yang and Zhaobing Gao
Journal of Pharmacology and Experimental Therapeutics December 1, 2014, 351 (3) 596-604; DOI: https://doi.org/10.1124/jpet.114.217703

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Research ArticleNeuropharmacology

NS1643 Rescues Both LQT2 and Epileptic Phenotypes

Ping Li, Xueqin Chen, Qiansen Zhang, Yueming Zheng, Hualiang Jiang, Huaiyu Yang and Zhaobing Gao
Journal of Pharmacology and Experimental Therapeutics December 1, 2014, 351 (3) 596-604; DOI: https://doi.org/10.1124/jpet.114.217703
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