Mruk K , Kobertz WR .

DC007669 NIDCD NIH HHS , R01 DC007669-04 NIDCD NIH HHS , R01 DC007669 NIDCD NIH HHS

	Figure 1. Modulation of Q1/E1 channels by boronates.(A) Time course of Q1/E1 current measured in ND96 at +40 mV at the end of a 2 s pulse. The current was normalized before compound application. Borax reversibly inhibits while methylboronic acid has little to no effect on channel current. Phenylboronic acid (PBA) initially inhibits current and then slowly potentiates. Benzoic acid reversibly reduces Q1/E1 channel current whereas benzyl alcohol reversibly activates the channel complex. (B) Families of currents recorded before and during treatment with PBA or benzyl alcohol. Currents were elicited by 4 s step test potentials from −80 to +60 mV in 10 mV increments from a holding potential of −80 mV followed by a tail pulse to −30 mV. Dashed line indicates zero current. Scale bars represent 1 µA and 0.5 s. (C) Voltage-activation curves for Q1/E1 calculated from tail current analysis. Solid curves represent Boltzmann fits to the data. Data are presented as the mean±SEM (n = 10).
	Figure 2. PBA activates Q1/E3 complexes.(A) Time course of Q1/E3 current measured in ND96 at +40 mV at the end of a 2 s pulse. The current was normalized before PBA application. PBA initially inhibits then slowly potentiates channel current. (B) Families of currents recorded in high external potassium (50 mM) before and during treatment with PBA. Currents were elicited by 2 s test potentials from −100 to +60 mV in 20 mV increments. The holding and tail potentials were −80 mV. Dashed line indicates zero current. Scale bars represent 1 µA and 0.5 s. (C) Voltage-activation curves for Q1/E3 calculated from tail current analysis. Solid curves represent Boltzmann fits to the data. Data are presented as the mean±SEM (n = 10).
	Figure 3. PBA activates all tested members of the KCNQ family.Left panel: Time courses of current recorded in ND96 at +40 mV at the end of a 2 s pulse. The current was normalized before PBA application. PBA initially inhibits and then slowly potentiates Q1 and Q2/Q3 current. PBA only activates Q4 channels. Middle panel: Families of currents recorded before and during treatment with PBA. Currents were elicited by 4 s test potentials from −100 to +60 mV in 10 mV increments from a holding potential of −80 mV followed by a tail pulse to −30 mV. Dashed line indicates zero current. Scale bars represent 1 µA and 0.5 s. Right panel: Voltage-activation curves calculated from tail current analysis. Solid curves represent Boltzmann fits to the data. Data are presented as the mean±SEM (n = 4–6).
	Figure 4. PBA inhibits other Kv channels.(A) Time course of Shaker (inactivation removed) current measured in ND96 at +40 mV, 100 ms pulse when 10 mM PBA was applied through the bath solution. (B) Families of Shaker currents recorded before and during treatment with PBA. Currents were elicited by 100 ms step test potentials from −100 to +60 mV in 10 mV increments from a holding potential of −80 mV. Dashed line indicates zero current. Scale bars represent 1 µA and 0.1 s. (C) Time course of hERG current measured in ND96 at 0 mV, 2 s pulse when 10 mM PBA was applied through the bath solution. (D) Families of hERG currents recorded before and during treatment with PBA. Currents were elicited by 2 s step test potentials from −100 to +60 mV in 10 mV increments from a holding potential of −80 mV. Dashed line indicates zero current. Scale bars represent 1 µA and 0.5 s.
	Figure 5. Activation of Q1 by PBA is dependent on the external charge carrier ion.Current traces were recorded in (A) 50 mM K+, (B) Rb+, or (C) Cs+. Left panel: Representative overlaid traces elicited by a +40 mV test and −80 mV tail pulse before and after the onset of PBA potentiation. Inset: Normalized tail currents comparing the deactivation kinetics before and after the onset of PBA potentiation. Tick marks represent 200 ms. Right panel: Time course of current recorded during the PBA potentiation phase. Outward current measured at the end of a 2 s pulse to +40 mV; maximal inward current measured during the −80 mV tail pulse. Time zero is the amount of current after initial inhibition but before potentiation by PBA. Data are represented as the mean±SEM (n = 5–10).

Abitbol, Stilbenes and fenamates rescue the loss of I(KS) channel function induced by an LQT5 mutation and other IsK mutants. 1999, Pubmed, Xenbase

Abitbol, Stilbenes and fenamates rescue the loss of I(KS) channel function induced by an LQT5 mutation and other IsK mutants. 1999, Pubmed , Xenbase
Barhanin, K(V)LQT1 and lsK (minK) proteins associate to form the I(Ks) cardiac potassium current. 1996, Pubmed , Xenbase
Baukrowitz, Use-dependent blockers and exit rate of the last ion from the multi-ion pore of a K+ channel. 1996, Pubmed
Bunn, The potential role of proteasome inhibitors in the treatment of lung cancer. 2004, Pubmed
Busch, The role of the IsK protein in the specific pharmacological properties of the IKs channel complex. 1997, Pubmed , Xenbase
Choi, Tetraethylammonium blockade distinguishes two inactivation mechanisms in voltage-activated K+ channels. 1991, Pubmed
Cooper, M-channels: neurological diseases, neuromodulation, and drug development. 2003, Pubmed
Gage, KCNE3 truncation mutants reveal a bipartite modulation of KCNQ1 K+ channels. 2004, Pubmed , Xenbase
Gao, Desensitization of chemical activation by auxiliary subunits: convergence of molecular determinants critical for augmenting KCNQ1 potassium channels. 2008, Pubmed
Gutman, International Union of Pharmacology. LIII. Nomenclature and molecular relationships of voltage-gated potassium channels. 2005, Pubmed
Jentsch, Neuronal KCNQ potassium channels: physiology and role in disease. 2000, Pubmed
Jespersen, The KCNQ1 potassium channel: from gene to physiological function. 2005, Pubmed
Kharkovets, KCNQ4, a K+ channel mutated in a form of dominant deafness, is expressed in the inner ear and the central auditory pathway. 2000, Pubmed
Kubisch, KCNQ4, a novel potassium channel expressed in sensory outer hair cells, is mutated in dominant deafness. 1999, Pubmed , Xenbase
Lerche, Molecular impact of MinK on the enantiospecific block of I(Ks) by chromanols. 2000, Pubmed , Xenbase
Li, Single-channel analysis of KCNQ K+ channels reveals the mechanism of augmentation by a cysteine-modifying reagent. 2004, Pubmed
Li, Regulation of Kv7 (KCNQ) K+ channel open probability by phosphatidylinositol 4,5-bisphosphate. 2005, Pubmed
MacKinnon, Mutations affecting TEA blockade and ion permeation in voltage-activated K+ channels. 1990, Pubmed
McCrossan, The MinK-related peptides. 2004, Pubmed , Xenbase
Mitcheson, A structural basis for drug-induced long QT syndrome. 2000, Pubmed , Xenbase
Mitcheson, Trapping of a methanesulfonanilide by closure of the HERG potassium channel activation gate. 2000, Pubmed , Xenbase
Nakajo, KCNE1 and KCNE3 stabilize and/or slow voltage sensing S4 segment of KCNQ1 channel. 2007, Pubmed , Xenbase
Neyroud, A novel mutation in the potassium channel gene KVLQT1 causes the Jervell and Lange-Nielsen cardioauditory syndrome. 1997, Pubmed
Panaghie, The role of S4 charges in voltage-dependent and voltage-independent KCNQ1 potassium channel complexes. 2007, Pubmed , Xenbase
Patthy, Reversible modification of arginine residues. Application to sequence studies by restriction of tryptic hydrolysis to lysine residues. 1975, Pubmed
Pusch, Gating and flickery block differentially affected by rubidium in homomeric KCNQ1 and heteromeric KCNQ1/KCNE1 potassium channels. 2000, Pubmed , Xenbase
Robbins, KCNQ potassium channels: physiology, pathophysiology, and pharmacology. 2001, Pubmed
Roche, Antibodies and a cysteine-modifying reagent show correspondence of M current in neurons to KCNQ2 and KCNQ3 K+ channels. 2002, Pubmed
Rocheleau, KCNE peptides differently affect voltage sensor equilibrium and equilibration rates in KCNQ1 K+ channels. 2008, Pubmed , Xenbase
Roepke, The KCNE2 potassium channel ancillary subunit is essential for gastric acid secretion. 2006, Pubmed
Salata, A novel benzodiazepine that activates cardiac slow delayed rectifier K+ currents. 1998, Pubmed , Xenbase
Sanguinetti, Coassembly of K(V)LQT1 and minK (IsK) proteins to form cardiac I(Ks) potassium channel. 1996, Pubmed , Xenbase
Schroeder, A constitutively open potassium channel formed by KCNQ1 and KCNE3. 2000, Pubmed , Xenbase
Schwake, Surface expression and single channel properties of KCNQ2/KCNQ3, M-type K+ channels involved in epilepsy. 2000, Pubmed , Xenbase
Seebohm, Molecular determinants of KCNQ1 channel block by a benzodiazepine. 2003, Pubmed , Xenbase
Seebohm, Tight coupling of rubidium conductance and inactivation in human KCNQ1 potassium channels. 2003, Pubmed , Xenbase
Selyanko, Properties of single M-type KCNQ2/KCNQ3 potassium channels expressed in mammalian cells. 2001, Pubmed
Sesti, Single-channel characteristics of wild-type IKs channels and channels formed with two minK mutants that cause long QT syndrome. 1998, Pubmed , Xenbase
Splawski, Spectrum of mutations in long-QT syndrome genes. KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. 2000, Pubmed
Xiong, Activation of Kv7 (KCNQ) voltage-gated potassium channels by synthetic compounds. 2008, Pubmed
Yang, Single-channel properties of IKs potassium channels. 1998, Pubmed , Xenbase
Yellen, Mutations affecting internal TEA blockade identify the probable pore-forming region of a K+ channel. 1991, Pubmed