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Electrophysiological characterization of human KCNT1 channel modulators and the therapeutic potential of hydroquinine and tipepidine in KCNT1 mutation-associated epilepsy mouse model

Acta Pharmacologica Sinica volume 46, pages 1190–1204 (2025)Cite this article

Abstract

Patients suffering epilepsy caused by the gain-of-function mutants of the hKCNT1 potassium channels are drug refractory. In this study, we cloned a novel human KCNT1B channel isoform using the brain cDNA library and conducted patch-clamp and molecular docking analyses to characterize the pharmacological properties of the hKCNT1B channel using thirteen drugs. Among cinchona alkaloids, we found that hydroquinine exerted the strongest blocking effect on the hKCNT1B channel, especially the F313L mutant. In addition, we confirmed the antitussive drug tipepidine was also a potent inhibitor of the hKCNT1B channel. Subsequently, we proved that these two drugs produced an excellent therapeutic effect on the epileptic model of KCNT1 Y777H mutant male mice; thus, both could be ready-to-use anti-epileptic drugs. On the other hand, we demonstrated that the activation of the KCNT1 channel by loxapine and clozapine was through interacting with pore domain residues to reverse the run-down of the KCNT1 channel. Taken together, our results provide new insights into the mechanism of the modulators in regulating the KCNT1 channel activity as well as important candidates for clinical tests in the treatment of KCNT1 mutant-associated epilepsy.

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Fig. 1: 4-AP and TEA block the hKCNT1B both intracellularly and extracellularly.
Fig. 2: Quinidine intracellularly and extracellularly blocks the hKCNT1B channel and its mutants.
Fig. 3: Comparison of the blockade of the hKCNT1B channel and F313L mutant by cinchona alkaloids.
Fig. 4: The blockades of the hKCNT1B channel by paxilline, VPA, and propofol.
Fig. 5: The blockade of hKCNT1B channels by tipepidine (TIP) and dextromethorphan (DXM).
Fig. 6: Hydroquinine and tipepidine effectively treated the spontaneous seizures of the KCNT1 Y777H mice.
Fig. 7: Loxapine reverses the rundown of the hKCNT1B channel.
Fig. 8: The 4-AP and TEA binding sites in Kv channels and the pore structure characters of BK channel family members.

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Acknowledgements

This work was supported by a Natural Science Foundation of China (NSFC) grant to ZZ (81471314 and 81671090), Natural Science Foundation of Jiangsu Province to ZZ (SBK201502515), Xuzhou Science and Technology Program (KC19036) to ZZ and (KC16H0230) to QYT, an NSFC grant to QYT (82371233). The Important Project of Natural Science in Colleges and Universities in Jiangsu Province to ZZ (14KJA320002), Jiangsu specially appointed professor to ZZ and QYT, We also appreciate the grant support from the Priority Academic Program Development of Jiangsu Higher Education Institutions and the Jiangsu Provincial Special Program of Medical Science (BL2014029). Jiangsu Province College Students’ Innovative Entrepreneurial Training Plan Program to YMW (202110313072). The general project of the developing grant for the Affiliated Hospital of Xuzhou Medical University to MJK (XYFM202330).

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  1. These authors contributed equally: Qing Guo, Jun Gan, En-ze Wang, Yu-ming Wei, Jie Xu.

Authors and Affiliations

  1. Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, 221004, China

    Qing Guo, Jun Gan, En-ze Wang, Yu-ming Wei, Jie Xu, Yun Xu, Fei-fei Zhang, Qiong-yao Tang & Zhe Zhang

  2. Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, 221004, China

    Qing Guo, Jun Gan, En-ze Wang, Yu-ming Wei, Jie Xu, Yun Xu, Fei-fei Zhang, Qiong-yao Tang & Zhe Zhang

  3. NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, Xuzhou, 221004, China

    Qing Guo, Jun Gan, En-ze Wang, Yu-ming Wei, Jie Xu, Yun Xu, Fei-fei Zhang, Qiong-yao Tang & Zhe Zhang

  4. Department of Pharmaceutical Sciences, Northeastern University, Boston, MA, 02115, USA

    Meng Cui

  5. Department of Anesthesiology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221000, China

    Meng-xing Jia

  6. Department of Anesthesiology, The Second Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221002, China

    Ming-jian Kong

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Contributions

QG, JG, EZW, and YMW performed research and analyzed the data. FFZ cloned the hKCNT1 channel. YX tested the electrophysiological property of the hKCNT1 channel. JX and MC generated the modeling structure. MJK and MXJ provided useful suggestions and supervised surgery. QYT and ZZ designed the experiment and wrote the paper. All authors have approved the final version of this manuscript.

Corresponding authors

Correspondence to Meng-xing Jia, Ming-jian Kong, Qiong-yao Tang or Zhe Zhang.

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The authors declare no competing interests.

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Guo, Q., Gan, J., Wang, Ez. et al. Electrophysiological characterization of human KCNT1 channel modulators and the therapeutic potential of hydroquinine and tipepidine in KCNT1 mutation-associated epilepsy mouse model. Acta Pharmacol Sin 46, 1190–1204 (2025). https://doi.org/10.1038/s41401-024-01457-8

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