Hodgkin, A. L. & Huxley, A. F. A quantitative description of membrane current and its application to conduction and excitation in nerve. J. Physiol. 117, 500–544 (1952).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Bean, B. P., Nowycky, M. C. & Tsien, R. W. β-Adrenergic modulation of calcium channels in frog ventricular heart cells. Nature 307, 371–375 (1984).

Article  CAS  PubMed  Google Scholar 

Liao, P., Yong, T. F., Liang, M. C., Yue, D. T. & Soong, T. W. Splicing for alternative structures of CaV1.2 Ca2+ channels in cardiac and smooth muscles. Cardiovasc. Res. 68, 197–203 (2005).

Article  CAS  PubMed  Google Scholar 

Hetzenauer, A., Sinnegger-Brauns, M. J., Striessnig, J. & Singewald, N. Brain activation pattern induced by stimulation of L-type Ca2+-channels: contribution of CaV1.3 and CaV1.2 isoforms. Neuroscience 139, 1005–1015 (2006).

Article  CAS  PubMed  Google Scholar 

Hemmerlein, B. et al. Overexpression of Eag1 potassium channels in clinical tumours. Mol. Cancer 5, 41 (2006).

Article  PubMed  PubMed Central  Google Scholar 

Fertleman, C. R. et al. SCN9A mutations in paroxysmal extreme pain disorder: allelic variants underlie distinct channel defects and phenotypes. Neuron 52, 767–774 (2006).

Article  CAS  PubMed  Google Scholar 

Nappi, M. et al. Gain of function due to increased opening probability by two KCNQ5 pore variants causing developmental and epileptic encephalopathy. Proc. Natl Acad. Sci. USA 119, e2116887119 (2022).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Barcia, G. et al. De novo gain-of-function KCNT1 channel mutations cause malignant migrating partial seizures of infancy. Nat. Genet. 44, 1255–1259 (2012).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Wulff, H., Christophersen, P., Colussi, P., Chandy, K. G. & Yarov-Yarovoy, V. Antibodies and venom peptides: new modalities for ion channels. Nat. Rev. Drug Discov. 18, 339–357 (2019).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Santos, R. et al. A comprehensive map of molecular drug targets. Nat. Rev. Drug Discov. 16, 19–34 (2017).

Article  CAS  PubMed  Google Scholar 

Bezanilla, F. The voltage sensor in voltage-dependent ion channels. Physiol. Rev. 80, 555–592 (2000).

Article  CAS  PubMed  Google Scholar 

Jensen, M. Ø. et al. Mechanism of voltage gating in potassium channels. Science 336, 229–233 (2012).

Article  CAS  PubMed  Google Scholar 

Labro, A. J., Lacroix, J. J., Villalba-Galea, C. A., Snyders, D. J. & Bezanilla, F. Molecular mechanism for depolarization-induced modulation of Kv channel closure. J. Gen. Physiol. 140, 481–493 (2012).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Gao, S. et al. Structural basis for human CaV1.2 inhibition by multiple drugs and the neurotoxin calciseptine. Cell 186, 5363–5374.e16 (2023).

Article  CAS  PubMed  Google Scholar 

Lenaeus, M., Gamal El-Din, T. M., Tonggu, L., Zheng, N. & Catterall, W. A. Structural basis for inhibition of the cardiac sodium channel by the atypical antiarrhythmic drug ranolazine. Nat. Cardiovasc. Res. 2, 587–594 (2023).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Li, X. et al. Structural basis for modulation of human NaV1.3 by clinical drug and selective antagonist. Nat. Commun. 13, 1286 (2022).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Vitali Serdoz, L., Rittger, H., Furlanello, F. & Bastian, D. Quinidine—a legacy within the modern era of antiarrhythmic therapy. Pharmacol. Res. 144, 257–263 (2019).

Article  CAS  PubMed  Google Scholar 

Grace Andrew, A. & Camm, A. J. Quinidine. N. Engl. J. Med. 338, 35–45 (1998).

Article  Google Scholar 

Wang, H.-S. et al. KCNQ2 and KCNQ3 potassium channel subunits: molecular correlates of the M-channel. Science 282, 1890–1893 (1998).

Article  CAS  PubMed  Google Scholar 

Jentsch, T. J. Neuronal KCNQ potassium channels: physiology and role in disease. Nat. Neurosci. 1, 21–30 (2000).

Article  CAS  Google Scholar 

Brown, D. A. & Adams, P. R. Muscarinic suppression of a novel voltage-sensitive K+ current in a vertebrate neurone. Nature 283, 673–676 (1980).

Article  CAS  PubMed  Google Scholar 

Mulkey, S. B. et al. Neonatal nonepileptic myoclonus is a prominent clinical feature of KCNQ2 gain-of-function variants R201C and R201H. Epilepsia 58, 436–445 (2017).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Millichap, J. J. et al. Infantile spasms and encephalopathy without preceding neonatal seizures caused by KCNQ2 R198Q, a gain-of-function variant. Epilepsia 58, e10–e15 (2017).

Article  CAS  PubMed  Google Scholar 

Miceli, F. et al. Early-onset epileptic encephalopathy caused by gain-of-function mutations in the voltage sensor of Kv7.2 and Kv7.3 potassium channel subunits. J. Neurosci. 35, 3782 (2015).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Miceli, F. et al. KCNQ2 R144 variants cause neurodevelopmental disability with language impairment and autistic features without neonatal seizures through a gain-of-function mechanism. eBioMedicine 81, 104130 (2022).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Fontán-Lozano, Á., Suárez-Pereira, I., Delgado-García, J. M. & Carrión, Á. M. The M-current inhibitor XE991 decreases the stimulation threshold for long-term synaptic plasticity in healthy mice and in models of cognitive disease. Hippocampus 21, 22–32 (2011).

Article  PubMed  Google Scholar 

Liu, H., Jia, L., Chen, X., Shi, L. & Xie, J. The Kv7/KCNQ channel blocker XE991 protects nigral dopaminergic neurons in the 6-hydroxydopamine rat model of Parkinson’s disease. Brain Res. Bull. 137, 132–139 (2018).

Article  CAS  PubMed  Google Scholar 

Li, X. et al. Molecular basis for ligand activation of the human KCNQ2 channel. Cell Res. 31, 52–61 (2021).

Article  CAS  PubMed  Google Scholar 

Zhang, Y.-M. et al. Discovery of HN37 as a potent and chemically stable antiepileptic drug candidate. J. Med. Chem. 64, 5816–5837 (2021).

Article  CAS  PubMed  Google Scholar 

Zhang, S. et al. A small-molecule activation mechanism that directly opens the KCNQ2 channel. Nat. Chem. Biol. 20, 847–856 (2024).

Article  CAS  PubMed  Google Scholar 

Smart, O. S., Neduvelil, J. G., Wang, X., Wallace, B. A. & Sansom, M. S. P. HOLE: a program for the analysis of the pore dimensions of ion channel structural models. J. Mol. Graph. 14, 354–360 (1996).

Article  CAS