Maghera J , Li J , Lamothe SM , Braun M , Appendino JP , Au PYB , Kurata HT .

                epilepsy

	Figure 1. Inheritance of Kv7.2 and Kv7.3 mutations associated with epilepsy. A, Mutations in Kv7.2 or Kv7.3 associated with a documented case of epilepsy (compiled from ClinVar or RIKEE databases) are highlighted on molecular models of each channel. Mutations are color coded based on severity (green = BFNE, red = epileptic encephalopathy or other severe outcomes). Mutations that do not map to structural elements defined in the KCNQ1 cryo‐EM structure have been omitted (VSD, voltage‐sensing domain, SF, selectivity filter, CaM, Calmodulin). B, Pattern of inheritance of a neonatal seizure phenotype in a family carrying the Kv7.3[T313I] mutation. Upper, sequence alignment of the reference KCNQ3 gene and Kv7.3 protein in relation to the proband. The identified mutation [T313I] is highlighted in bold type. Lower, pedigree for the family characterized in our study with filled symbols indicating affected individuals
	Figure 2. v7.3[T313I] abolishes Kv7.3 function. A, Molecular model of essential intersubunit hydrogen bond between conserved residues T313 and Y319 located in the selectivity signature sequence. B, Two‐electrode voltage‐clamp recordings from Xenopus laevis oocytes expressing Kv7.3[A315T] and Kv7.3[A315T][T313I]. Oocytes were held at −80 mV and depolarized for 1.5s to voltages between −140 mV and +40 mV (in 10‐mV steps) followed by repolarization to −20 mV test pulse. Current amplitudes at +20 mV of Kv7.3 [A315T] and Kv7.3[A315T] [T313I] were compared using a student’s t test (* indicates P<0.05 relative to A315T alone)
	Figure 3. Co‐expression with Kv7.2 and Kv7.3[T313I] reduces heteromeric channel function with no effect on gating. A, Two‐electrode voltage‐clamp sample traces from oocytes expressing various combinations of Kv7.2 and Kv7.3 (injected with a total of 50 ng of mRNA per group). The voltage step protocol is the same as Figure 2B. B, Current amplitudes after a 1.5 s + 20 mV voltage step. Current magnitudes were compared using one‐way ANOVA, followed by Tukey’s post hoc test (* indicates P < 0.05). C, Conductance‐voltage relationships were collected using the protocol in panel (A), using tail current magnitudes (−20 mV) to assess the extent of channel opening during the conditioning step. Fitted gating parameters were (mean ± S.E.M.): for Kv7.2 + Kv7.3 +[T313I], k = 9.4 ± 0.3 mV, V1/2 = −30 ± 1 mV; for Kv7.2 + [T313I], k = 9.1 ± 0.3 mV, V1/2 = −35.1 ± 0.5 mV; for Kv7.2 + Kv7.3, k = 10.2 ± 0.3 mV, V1/2 = −34.2 ± 0.3 mV; for Kv7.2 homomers, k = 9.2 ± 0.2 mV, V1/2 = −34.2 ± 0.6 mV. No significant differences in gating parameters were detected
	Figure 4. Reduced ICA‐069673 sensitivity of Kv7.2/Kv7.3[T313I] heteromeric channels. A, Example currents of two‐electrode voltage‐clamp recordings. Oocytes were depolarized to +20 mV and repolarized for 12 s in a step‐down manner (−20 mV per sweep), followed by another +20 mV depolarizing pulse to determine instantaneous current at −100 mV. Currents within the dashed box are illustrated on an expanded time scale in the right panels, showing the assessment of instantaneous current levels in different experimental conditions. B, Fractional instantaneous current after incubation with 100 μmol/L ICA‐069673 was measured as indicated by the arrows in panel (A), data are shown as mean ± SEM. C, Fractional instantaneous current (repolarization voltage of −100 mV) for various combinations of Kv7.2, Kv7.3, and Kv7.3[T313I], shown on a cell‐by‐cell basis (Kruskal‐Wallis one‐way ANOVA on ranks, * indicates P < 0.05 relative to Kv7.2 homomeric channels)
	Figure 5. Variable outcomes of homologous selectivity filter mutations in Kv7.2 and Kv7.3. A, Current magnitude was measured at +20 mV in Xenopus oocytes injected with Kv7.2 + Kv7.3, or various combinations of channel mutants and their wild‐type counterpart, as indicated. Currents were recording 48‐56 h after injection (n = 10 per condition, one‐way ANOVA on ranks and Tukey post hoc test, # indicates P < 0.05 relative to Kv7.2/Kv7.3, * indicates P < 0.05 relative to Kv7.2/Kv7.3[T313I]). B, Instantaneous tail current magnitudes were recorded as described in Figure 4 in the presence of 100 μmol/L ICA‐069673, for all possible combinations of injected channels (note that Kv7.3 + Kv7.2[T274I] did not yield current sizes that could be confidently assessed or analyzed)

Adams, Synaptic inhibition of the M-current: slow excitatory post-synaptic potential mechanism in bullfrog sympathetic neurones. 1982, Pubmed

Adams, Synaptic inhibition of the M-current: slow excitatory post-synaptic potential mechanism in bullfrog sympathetic neurones. 1982, Pubmed
Bal, Homomeric and heteromeric assembly of KCNQ (Kv7) K+ channels assayed by total internal reflection fluorescence/fluorescence resonance energy transfer and patch clamp analysis. 2008, Pubmed
Bassi, Functional analysis of novel KCNQ2 and KCNQ3 gene variants found in a large pedigree with benign familial neonatal convulsions (BFNC). 2005, Pubmed
Biervert, A potassium channel mutation in neonatal human epilepsy. 1998, Pubmed , Xenbase
Brown, Muscarinic suppression of a novel voltage-sensitive K+ current in a vertebrate neurone. 1980, Pubmed
Castaldo, Benign familial neonatal convulsions caused by altered gating of KCNQ2/KCNQ3 potassium channels. 2002, Pubmed , Xenbase
Charlier, A pore mutation in a novel KQT-like potassium channel gene in an idiopathic epilepsy family. 1998, Pubmed
Delmas, Pathways modulating neural KCNQ/M (Kv7) potassium channels. 2005, Pubmed
Doyle, The structure of the potassium channel: molecular basis of K+ conduction and selectivity. 1998, Pubmed
Etxeberria, Three mechanisms underlie KCNQ2/3 heteromeric potassium M-channel potentiation. 2004, Pubmed , Xenbase
Fisher, ILAE official report: a practical clinical definition of epilepsy. 2014, Pubmed
Goto, Characteristics of KCNQ2 variants causing either benign neonatal epilepsy or developmental and epileptic encephalopathy. 2019, Pubmed
Gómez-Posada, A pore residue of the KCNQ3 potassium M-channel subunit controls surface expression. 2010, Pubmed , Xenbase
Hadley, Differential tetraethylammonium sensitivity of KCNQ1-4 potassium channels. 2000, Pubmed
Hirose, A novel mutation of KCNQ3 (c.925T-->C) in a Japanese family with benign familial neonatal convulsions. 2000, Pubmed
Jentsch, Neuronal KCNQ potassium channels: physiology and role in disease. 2000, Pubmed
Kanaumi, Developmental changes in KCNQ2 and KCNQ3 expression in human brain: possible contribution to the age-dependent etiology of benign familial neonatal convulsions. 2008, Pubmed
Karczewski, The mutational constraint spectrum quantified from variation in 141,456 humans. 2020, Pubmed
Kurata, A structural interpretation of voltage-gated potassium channel inactivation. 2006, Pubmed
Lauritano, A novel homozygous KCNQ3 loss-of-function variant causes non-syndromic intellectual disability and neonatal-onset pharmacodependent epilepsy. 2019, Pubmed
Lezmy, M-current inhibition rapidly induces a unique CK2-dependent plasticity of the axon initial segment. 2017, Pubmed
Li, Heteromeric Assembly of Truncated Neuronal Kv7 Channels: Implications for Neurologic Disease and Pharmacotherapy. 2020, Pubmed , Xenbase
MacKinnon, Mutations affecting TEA blockade and ion permeation in voltage-activated K+ channels. 1990, Pubmed
Milh, Variable clinical expression in patients with mosaicism for KCNQ2 mutations. 2015, Pubmed
Milh, Similar early characteristics but variable neurological outcome of patients with a de novo mutation of KCNQ2. 2013, Pubmed
Millichap, KCNQ2 encephalopathy: Features, mutational hot spots, and ezogabine treatment of 11 patients. 2016, Pubmed
Orhan, Dominant-negative effects of KCNQ2 mutations are associated with epileptic encephalopathy. 2014, Pubmed , Xenbase
Perozo, Gating currents from a nonconducting mutant reveal open-closed conformations in Shaker K+ channels. 1993, Pubmed
Pless, Hydrogen bonds as molecular timers for slow inactivation in voltage-gated potassium channels. 2013, Pubmed
Robbins, Effects of KCNQ2 gene truncation on M-type Kv7 potassium currents. 2013, Pubmed
Rogawski, KCNQ2/KCNQ3 K+ channels and the molecular pathogenesis of epilepsy: implications for therapy. 2000, Pubmed
Sands, Rapid and safe response to low-dose carbamazepine in neonatal epilepsy. 2016, Pubmed
Scheffer, ILAE classification of the epilepsies: Position paper of the ILAE Commission for Classification and Terminology. 2017, Pubmed
Schroeder, Moderate loss of function of cyclic-AMP-modulated KCNQ2/KCNQ3 K+ channels causes epilepsy. 1998, Pubmed , Xenbase
Selyanko, Inhibition of KCNQ1-4 potassium channels expressed in mammalian cells via M1 muscarinic acetylcholine receptors. 2000, Pubmed
Shah, Molecular correlates of the M-current in cultured rat hippocampal neurons. 2002, Pubmed
Shih, High-level expression and detection of ion channels in Xenopus oocytes. 1998, Pubmed , Xenbase
Singh, KCNQ2 and KCNQ3 potassium channel genes in benign familial neonatal convulsions: expansion of the functional and mutation spectrum. 2003, Pubmed , Xenbase
Singh, A novel potassium channel gene, KCNQ2, is mutated in an inherited epilepsy of newborns. 1998, Pubmed
Soh, Deletion of KCNQ2/3 potassium channels from PV+ interneurons leads to homeostatic potentiation of excitatory transmission. 2018, Pubmed
Soldovieri, Early-onset epileptic encephalopathy caused by a reduced sensitivity of Kv7.2 potassium channels to phosphatidylinositol 4,5-bisphosphate. 2016, Pubmed
Soldovieri, Novel KCNQ2 and KCNQ3 mutations in a large cohort of families with benign neonatal epilepsy: first evidence for an altered channel regulation by syntaxin-1A. 2014, Pubmed
Stewart, The Kv7.2/Kv7.3 heterotetramer assembles with a random subunit arrangement. 2012, Pubmed
Sun, Cryo-EM Structure of a KCNQ1/CaM Complex Reveals Insights into Congenital Long QT Syndrome. 2017, Pubmed , Xenbase
Tinel, The KCNQ2 potassium channel: splice variants, functional and developmental expression. Brain localization and comparison with KCNQ3. 1998, Pubmed
Tzingounis, The KCNQ5 potassium channel mediates a component of the afterhyperpolarization current in mouse hippocampus. 2010, Pubmed , Xenbase
Wang, Four drug-sensitive subunits are required for maximal effect of a voltage sensor-targeted KCNQ opener. 2018, Pubmed
Wang, Pore- and voltage sensor-targeted KCNQ openers have distinct state-dependent actions. 2018, Pubmed
Wang, KCNQ2 and KCNQ3 potassium channel subunits: molecular correlates of the M-channel. 1998, Pubmed , Xenbase
Weckhuysen, KCNQ2 encephalopathy: emerging phenotype of a neonatal epileptic encephalopathy. 2012, Pubmed
Yang, How does the W434F mutation block current in Shaker potassium channels? 1997, Pubmed , Xenbase
Yang, Functional expression of two KvLQT1-related potassium channels responsible for an inherited idiopathic epilepsy. 1998, Pubmed , Xenbase
Zhou, Chemistry of ion coordination and hydration revealed by a K+ channel-Fab complex at 2.0 A resolution. 2001, Pubmed