Cernuda B , Fernandes CT , Allam SM , Orzillo M , Suppa G , Chia Chang Z , Athanasopoulos D , Buraei Z .

R15 GM124013 NIGMS NIH HHS

             membrane repolarization during cardiac muscle cell action potential

	Fig 1. Dose-response curve for R-roscovitine inhibition of WT hERG channels. A) Skeletal formula of R-roscovitine, 2-(1-ethyl-2-hydroxyethylamino)-6-benzylamino-9-isopropylpurine. B) Pulse protocol (top) along with representative traces from a WT cell (bottom) exposed to the indicated R-roscovitine concentrations. Channels were activated with a 1-second step to +40 mV from -80 mV, and tail currents (◊) were elicited by a 1-second repolarization to -50 mV. The single 2-second episodic pulse was repeated for 3.44 minutes as the various concentrations were washed in and out of the gravity-fed perfusion system. C) Time-course of tail current inhibition (measured from ◊, in B) from a representative cell expressing WT hERG in the presence of the indicated R-roscovitine concentrations. D) Fractional block data were fitted with a Hill equation (see methods) to obtain the IC50 for WT hERG (196 ± 12 μM, n = 11). Error bars here and elsewhere represent standard errors.
	Fig 2. Characteristics of R-roscovitine inhibition of hERG channels. A) Voltage protocol and current traces from a representative cell expressing hERG channels before (Control) and during 200 μM R-roscovitine application. From a holding potential of -80 mV, outward currents were elicited at two phases: depolarization (from -50 mV to +60 mV) and repolarization (to -50 mV). Mean step currents were measured at the end of the 2-second step (▽) and tail currents were measured from their peak (◊). B) Normalized I-V curves for Control and 200 μM R-roscovitine from mean step currents (▽, n = 14). Inhibition was strongest between -30 mV and +30 mV, a range where the open state is more prevalent than either the closed or inactivated state. C) Average percent step current inhibition by 200 μM R-roscovitine at various step voltages. Inhibition was weakest at voltages where channels are closed (-50 mV) or inactivated (+50 mV; p = 0.0052 for 0 vs. -50 mV, p < 0.0001 for 0 vs. +50 mV, n = 14, one-way ANOVA). D) Tail I-V curves for Control and 200 μM R-roscovitine, with normalized peak tail currents (◊, n = 14). Smooth lines are Boltzmann fits to the activation curves, which produced significantly different V0.5 (Ctrl: -16.5 ± 1.1 mV, Rosc: -19.4 ± 1.1 mV; p = 0.0105, n = 14, paired t-test) and slopes (Ctrl: 11.7 ± 0.5, Rosc: 10.6 ± 0.5; p = 0.0114; n = 14, paired t-test). The dashed line shows a scaled activation curve in the presence of R-roscovitine. E) Average percent tail current inhibition by 200 μM R-roscovitine at various step voltages. The inhibition of tail current significantly increased with rising levels of depolarized potentials (p = 0.0134 for -40 vs. 0 mV, p = 0.0004 for -40 vs. +60 mV, n = 14, one-way ANOVA). Error bars represent standard errors; when not visible, error bars are smaller than the symbols. * = P < 0.05, ** = P < 0.01, and *** = P < 0.001.
	Fig 3. Comparison of unaffected step and tail currents from WT hERG, S624A, and Y652A hERG mutants. A) Step I-V curves for WT (○, blue), S624A (□, red), and Y652A (△, green) from a step depolarization protocol (top; currents measured at ▽). Rectification of S624A currents was reduced in comparison to WT current, with more than twice the amount of normalized current remaining for S624A (0.77 ± 0.06) compared to WT (0.28 ± 0.04) at +60 mV. B) WT, S624A, and Y652A tail I-V curves from a step depolarization protocol (top; currents measured at ◊). Boltzmann fits generated the following V0.5 of activation (neither of which were different from WT; p > 0.8 for WT-mutant comparisons): WT V0.5 = -16.5 ± 1.1 mV, S624A V0.5 = -17.7 ± 3.2 mV, and Y652A V0.5 = -16.5 ± 1.0 mV. The slopes for the activation curves were 11.7 ± 0.45 for WT, 16.3 ± 1.62 for S624A (p = 0.0033 compared to WT), and 12.5 ± 0.84 for Y652A (p = 0.7913 compared to WT); nWT = 14, nS624A = 9, nY652A = 9, one-way ANOVAs.
	Fig 4. S624A hERG channels have an increased sensitivity to R-roscovitine. A) Voltage protocol and representative current traces, from a cell expressing S624A hERG, before and during 200 μM R-roscovitine application. Note that tail currents were greatly diminished upon R-roscovitine application. B) S624A step I-V curves before and during 200 μM R-roscovitine application (currents measured at ▽ in A). The strongest inhibition occurred between -30 mV and +30 mV. C) Percent step inhibition of WT and S624A at varying step voltages. S624A was inhibited more potently than WT at intermediate voltages, where open probability is high (p < 0.05 for WT vs. S624A between -20 mV and 0 mV, nWT = 14, nS624A = 9, one-way ANOVA). D) S624A tail I-V curves measured at ◊. Smooth lines are Boltzmann fits that generated V0.5 of activation in Control: -17.7 ± 3.2 mV and in R-roscovitine: -3.3 ± 6.1 mV; ns, p = 0.09. The slopes were 16.3 ± 1.6 in Control, and 44.5 ± 3.3 in R-roscovitine (p < 0.0001; n = 9, paired t-tests). Dashed line indicates the fit to normalized currents in R-roscovitine. E) Percent tail inhibition of WT and S624A. When compared to WT over a range of voltages, levels of S624A tail current inhibition were much larger (p < 0.05 for WT vs. S624A between -20 mV and +50 mV, nWT = 14, nS624A = 9, one-way ANOVA). F) Concentration-response relationship for S624A. The S624A IC50 (152 ± 22 μM) was not significantly lower than the WT IC50 (196 ± 12 μM;p = 0.8323 for WT vs. S624A) but the dose-response slope for S624A was statistically smaller (0.84 ± 0.08 vs 1.5 ± 0.1 for WT; p = 0.0003, nWT = 11, nS624A = 9, one-way ANOVA). ** = P < 0.01, and *** = P < 0.001.
	Fig 5. The Y652A mutation attenuates hERG inhibition by R-roscovitine. A) Voltage protocol and representative current traces of a cell expressing Y652A hERG before and during 200 μM R-roscovitine application. B) Y652A step I-V curves before and during 200 μM R-roscovitine inhibition (currents measured at ▽). The curves were bell-shaped and displayed inhibition at intermediate voltages. C) Percent step inhibition of WT currents were much stronger than that of Y652A between -20 mV and +10 mV (p < 0.05 for WT vs. Y652A, nWT = 14, nY652A = 9, one-way ANOVA). D) Boltzmann fits of the Y652A tail I-V curves from the step depolarization protocol (currents measured at ◊) showed a significant shift in V0.5 and slopes for the Ctrl vs Rosc activation curves. Ctrl V0.5 = -16.5 ± 1.0 mV, and a Rosc V0.5 = -19.6 ± 0.5 mV (p = 0.0094), and activation slopes were 12.5 ± 0.8 for Ctrl and 9.3 ± 0.3 for Rosc. (p = 0.0025, n = 11, paired t-tests). Dashed line indicates the fit to normalized currents in R-roscovitine. E) Percent tail inhibition of WT and Y652A at their respective step voltages. Levels of Y652A tail current inhibition were significantly reduced compared to WT between -20 mV and +60 mV (p < 0.05 for WT vs. Y652A, nWT = 14, nY652A = 9, one-way ANOVA). F) Concentration-response relationship for Y652A. When compared to WT IC50 (196 ± 12 μM), Y652A had a ~ 2.9-fold increase in IC50 (567 ± 122 μM; p = 0.0005). The slope of the dose response curve significantly changed from 1.522 ± 0.1 for WT to 1.0 ± 0.14 for Y652A (p = 0.0052; nWT = 11, nY652A = 8, one-way ANOVAs). * = P < 0.05, ** = P < 0.01, and *** = P < 0.001.
	Fig 6. Weaker hERG current inhibition in the high K+ solution. A) Representative WT tail currents in high K+ prior to (Control) and during the indicated R-roscovitine concentrations, elicited by the protocol above. Tail currents from the dashed boxed region are expanded for clarity. B) Time course of inhibition from the cell in A. Peak tail currents were measured at ▽ during which the indicated R-roscovitine concentrations were applied and washed off. Peak tail currents were plotted over time. C) The IC50 for WT hERG in high K+ was 513 ± 43 μM (n = 9), which was significantly different from WT in low K+ (p <0.0001); the slopes (high K+ = 1.1 ± 0.2) were not (low K+ = 1.5 ± 0.1; p = 0.091, unpaired t-tests). D) Voltage protocol and representative current traces of a cell before (Ctrl) and during 500 μM R-roscovitine application. E) WT tail I-V curves from currents measured at ◊ in D. The smooth quadratic fits yielded a reversal potential (Erev) of -11.1 ± 3.3 mV in control, and -14.6 ± 2.4 mV in 500 μM R-roscovitine (p = 0.0237, n = 10, paired t-test). F) Percent tail inhibition calculated from E. Inhibition was significantly stronger at lower voltages than at high voltages (p = 0.0004 for +20 mV vs. -120 mV, p = 0.0002 for +20 mV vs. -80 mV, n = 10, one-way ANOVA). *** = P < 0.001.
	Fig 7. T623A hERG reduces R-roscovitine mediated inhibition. A) Voltage protocol and representative current traces of a cell expressing T623A before (Control) and during 500 μM R-roscovitine application. B) T623A tail I-V curves during the step repolarization protocol (currents measured at ◊). Quadratic fits generated Erev values (Ctrl = -39.7 ± 2.0 mV, Rosc = -40.1 ± 2.1 mV) that did not show a significant shift occurring with 500 μM R-roscovitine (p = 0.5995 for Ctrl vs. Rosc, n = 10, paired t-test). C) Percent tail inhibition of T623A hERG was significantly weaker over a range of voltages than WT inhibition (p < 0.05 for WT vs. T623A between +20 mV and -120 mV (excluding voltages close to the reversal potential; nWT = 10, nT623A = 10, one-way ANOVA). D) Compared to the WT IC50 (513 ± 43 μM), T623A IC50 was ~ 5.5-fold larger (2786 ± 488 μM; p = 0.0092) while the slope factor had a non-significant change from 1.1± 0.22 for WT to 0.7 ± 0.09 for T623A (p = 0.4901; nWT = 9, nT623A = 7, Kruskal-Wallis tests). * = P < 0.05, ** = P < 0.01, and *** = P < 0.001.
	Fig 8. R-roscovitine inhibition is almost completely abolished in F656A hERG. A) Voltage protocol and representative current traces of a cell expressing F656A before (Control) and during 500 μM R-roscovitine application. B) F656A tail I-V curves during the step repolarization protocol (currents measured at ◊). Quadratic fits generated to obtain Erev values (Ctrl = -45.1 ± 1.1 mV, Rosc = -42.1 ± 1.7 mV) did in fact show a shift with drug block (p = 0.02, n = 9, paired t-test). C) F656A tail current inhibition was almost non-existent for most repolarized voltages, which was a substantial difference from WT inhibition (p < 0.01 for WT vs. F656A between +20 mV and -120 mV (excluding points close to the reversal potential), nWT = 10, nF656A = 9, one-way ANOVA). D) Concentration-response relationship for F656A hERG IC50 (21.5 ± 10.6 mM) shows a ~ 42-fold increase from WT IC50 (513 ± 43 μM; p = 0.0004); and a significant reduction in the slope of the Hill equation from 1.1 ± 0.22 for WT to 0.42 ± 0.04 for F656; p < 0.005; nWT = 9, nF656A = 5, Kruskal-Wallis tests. ** = P < 0.01, and *** = P < 0.001.
	Fig 9. Deactivation time constants for hERG and its mutants. A) Representative traces from the indicated hERG constucts at -100 and -120 mV repolarization voltages. Tail currents (from the dash-boxed region of the voltage protocol) were fitted with a standard biexponential equation (red dashed line) to measure deactivation time constants (see methods). B) Average τfast for S624A, Y652A and T623A constructs at -120 mV were all significantly smaller than their respective WT controls (p = 0.0082, p = 0.0134, and p < 0.0001 respectively). At -100 mV, Y652A and T623A were significantly different from their respective WT controls (p = 0.0054 and p = 0.0009), while S624A was not (p = 0.0953). F656A was not different from WTHigh K+ (p = 0.4973 at -120 mV and p = 0.9430 at -100 mV). N = 6–10; one-way ANOVAs. C) τfast before (Control) and during R-roscovitine application at -120 mV. R-roscovitine sped up deactivation for WT (p = 0.0034) and T623A (p = 0.0009), but not for S624A (p = 0.312), Y652A (p = 0.2739), or F656A (p = 0.1708). N = 6–10; paired t-tests. R-roscovitine concentration was 200 μM for low K+ and 500 μM for high K+ solutions. * = P < 0.05, ** = P < 0.01, and *** = P < 0.001.
	S1 Fig. Step repolarization protocols for WT, S624A, and Y652A in the presence or absence of R-roscovitine. A) Representative current traces elicited from the step repolarization voltage protocol shown to the left. WT, S624A, and Y652A tail currents were measured at their peak ( ) in the absence (top row) and presence of 200 µM R-roscovitine (bottom row). B) Maximal tail current amplitudes from A were plotted against the repolarization voltage to show reversal potentials, which were then compared between control and R-roscovitine. The shifts for WT (Erev = -80.16 ± 1.31 to -76.7 ± 1.33 mV; p = 0.0294, paired t-test) and S624A (Erev = -82.25 ± 1.27 mV to -77.17 ± 2.00 mV; p = 0.0301, paired t-test) were significant, but not for Y652A (Erev = -81.08 ± 1.28 mV to -80.61 ± 2.12 mV; p = 0.6238, paired t-test). C) Percent inhibition of tail currents during the step repolarization protocol, which were calculated from the values in B (* = P < 0.05, ** = P < 0.01; one-way ANOVAs). nWT = 14, and nS624A,Y652A = 9.

Armstrong, Interaction of tetraethylammonium ion derivatives with the potassium channels of giant axons. 1971, Pubmed

Armstrong, Interaction of tetraethylammonium ion derivatives with the potassium channels of giant axons. 1971, Pubmed
Barrows, Extracellular potassium dependency of block of HERG by quinidine and cisapride is primarily determined by the permeant ion and not by inactivation. 2009, Pubmed , Xenbase
Benson, A phase I trial of the selective oral cyclin-dependent kinase inhibitor seliciclib (CYC202; R-Roscovitine), administered twice daily for 7 days every 21 days. 2007, Pubmed
Buraei, Roscovitine differentially affects CaV2 and Kv channels by binding to the open state. 2007, Pubmed
Chemi, Computational Tool for Fast in silico Evaluation of hERG K+ Channel Affinity. 2017, Pubmed
Choe, A novel hypothesis for the binding mode of HERG channel blockers. 2006, Pubmed
Clancy, Inherited and acquired vulnerability to ventricular arrhythmias: cardiac Na+ and K+ channels. 2005, Pubmed
Colenso, Interactions between voltage sensor and pore domains in a hERG K+ channel model from molecular simulations and the effects of a voltage sensor mutation. 2013, Pubmed
Curran, A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome. 1995, Pubmed
Dallakyan, Small-molecule library screening by docking with PyRx. 2015, Pubmed
De Azevedo, Inhibition of cyclin-dependent kinases by purine analogues: crystal structure of human cdk2 complexed with roscovitine. 1997, Pubmed
Dempsey, Assessing hERG pore models as templates for drug docking using published experimental constraints: the inactivated state in the context of drug block. 2014, Pubmed
Drew, Practice standards for electrocardiographic monitoring in hospital settings: an American Heart Association scientific statement from the Councils on Cardiovascular Nursing, Clinical Cardiology, and Cardiovascular Disease in the Young: endorsed by the International Society of Computerized Electrocardiology and the American Association of Critical-Care Nurses. 2004, Pubmed
Du, Ranolazine inhibition of hERG potassium channels: drug-pore interactions and reduced potency against inactivation mutants. 2014, Pubmed
Durdagi, Combined receptor and ligand-based approach to the universal pharmacophore model development for studies of drug blockade to the hERG1 pore domain. 2011, Pubmed
El Harchi, Molecular determinants of hERG potassium channel inhibition by disopyramide. 2012, Pubmed
Fan, Direct inhibition of P/Q-type voltage-gated Ca2+ channels by Gem does not require a direct Gem/Cavbeta interaction. 2010, Pubmed , Xenbase
Farid, New insights about HERG blockade obtained from protein modeling, potential energy mapping, and docking studies. 2006, Pubmed
Fernandez, Physicochemical features of the HERG channel drug binding site. 2004, Pubmed , Xenbase
Ficker, Molecular determinants of dofetilide block of HERG K+ channels. 1998, Pubmed , Xenbase
Forli, A force field with discrete displaceable waters and desolvation entropy for hydrated ligand docking. 2012, Pubmed
Ganapathi, State-dependent block of HERG potassium channels by R-roscovitine: implications for cancer therapy. 2009, Pubmed
Gualdani, Inhibition of hERG potassium channel by the antiarrhythmic agent mexiletine and its metabolite m-hydroxymexiletine. 2015, Pubmed
Hanwell, Avogadro: an advanced semantic chemical editor, visualization, and analysis platform. 2012, Pubmed
He, Current pharmacogenomic studies on hERG potassium channels. 2013, Pubmed
Helliwell, Structural implications of hERG K+ channel block by a high-affinity minimally structured blocker. 2018, Pubmed
Hosaka, Mutational analysis of block and facilitation of HERG current by a class III anti-arrhythmic agent, nifekalant. 2007, Pubmed , Xenbase
Huang, Cardiac voltage-gated ion channels in safety pharmacology: Review of the landscape leading to the CiPA initiative. 2017, Pubmed
Jiang, X-ray structure of a voltage-dependent K+ channel. 2003, Pubmed
Kamiya, Molecular determinants of hERG channel block by terfenadine and cisapride. 2008, Pubmed , Xenbase
Kamiya, Open channel block of HERG K(+) channels by vesnarinone. 2001, Pubmed , Xenbase
Kamiya, Molecular determinants of HERG channel block. 2006, Pubmed , Xenbase
Karagueuzian, Enhanced Late Na and Ca Currents as Effective Antiarrhythmic Drug Targets. 2017, Pubmed
Kim, Trigger-specific risk factors and response to therapy in long QT syndrome type 2. 2010, Pubmed
Kim, Effect of sibutramine HCl on cardiac hERG K+ channel. 2009, Pubmed
Knape, In silico analysis of conformational changes induced by mutation of aromatic binding residues: consequences for drug binding in the hERG K+ channel. 2011, Pubmed
Kozik, Acquired long QT syndrome: frequency, onset, and risk factors in intensive care patients. 2012, Pubmed
Kramer, MICE models: superior to the HERG model in predicting Torsade de Pointes. 2013, Pubmed
Kratz, Natural products modulating the hERG channel: heartaches and hope. 2017, Pubmed
Kubala, Flavonolignans As a Novel Class of Sodium Pump Inhibitors. 2016, Pubmed
Langlois, Pituitary-Directed Therapies for Cushing's Disease. 2018, Pubmed
Lei, Two components of the delayed rectifier potassium current, IK, in rabbit sino-atrial node cells. 1996, Pubmed
Maher, Novel Pyrazolo[3,4-d]pyrimidines as Potential Cytotoxic Agents: Design, Synthesis, Molecular Docking and CDK2 Inhibition. 2019, Pubmed
McClue, In vitro and in vivo antitumor properties of the cyclin dependent kinase inhibitor CYC202 (R-roscovitine). 2002, Pubmed
Meijer, Biochemical and cellular effects of roscovitine, a potent and selective inhibitor of the cyclin-dependent kinases cdc2, cdk2 and cdk5. 1997, Pubmed , Xenbase
Milnes, Blockade of HERG potassium currents by fluvoxamine: incomplete attenuation by S6 mutations at F656 or Y652. 2003, Pubmed
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
Morris, AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. 2009, Pubmed
Mullins, Extracellular sodium interacts with the HERG channel at an outer pore site. 2002, Pubmed
Ng, Insights into hERG K+ channel structure and function from NMR studies. 2013, Pubmed
Osterberg, Exploring blocker binding to a homology model of the open hERG K+ channel using docking and molecular dynamics methods. 2005, Pubmed
Perrin, Drug binding to the inactivated state is necessary but not sufficient for high-affinity binding to human ether-à-go-go-related gene channels. 2008, Pubmed
Perry, Structural determinants of HERG channel block by clofilium and ibutilide. 2004, Pubmed , Xenbase
Pettersen, UCSF Chimera--a visualization system for exploratory research and analysis. 2004, Pubmed
Pillozzi, HERG potassium channels are constitutively expressed in primary human acute myeloid leukemias and regulate cell proliferation of normal and leukemic hemopoietic progenitors. 2002, Pubmed
Piper, Gating currents associated with intramembrane charge displacement in HERG potassium channels. 2003, Pubmed , Xenbase
Prinz, Hill coefficients, dose-response curves and allosteric mechanisms. 2010, Pubmed
Rao, Voltage-gated ion channels in cancer cell proliferation. 2015, Pubmed
Raynaud, In vitro and in vivo pharmacokinetic-pharmacodynamic relationships for the trisubstituted aminopurine cyclin-dependent kinase inhibitors olomoucine, bohemine and CYC202. 2005, Pubmed
Reinelt, Incidence and type of cardiac arrhythmias in critically ill patients: a single center experience in a medical-cardiological ICU. 2001, Pubmed
Rodriguez-Menchaca, Block of HERG channels by berberine: mechanisms of voltage- and state-dependence probed with site-directed mutant channels. 2006, Pubmed , Xenbase
Sánchez-Chapula, Molecular determinants of voltage-dependent human ether-a-go-go related gene (HERG) K+ channel block. 2002, Pubmed , Xenbase
Sanguinetti, hERG potassium channels and cardiac arrhythmia. 2006, Pubmed
Sanguinetti, HERG1 channelopathies. 2010, Pubmed
Sanguinetti, A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the IKr potassium channel. 1995, Pubmed , Xenbase
Saxena, New potential binding determinant for hERG channel inhibitors. 2016, Pubmed
Schutte, The effect of the cyclin-dependent kinase inhibitor olomoucine on cell cycle kinetics. 1997, Pubmed
Seeliger, Discovery of novel human aquaporin-1 blockers. 2013, Pubmed , Xenbase
Senderowicz, Novel small molecule cyclin-dependent kinases modulators in human clinical trials. 2003, Pubmed
Shin, A novel assessment of nefazodone-induced hERG inhibition by electrophysiological and stereochemical method. 2014, Pubmed
Siebrands, Local anesthetic interaction with human ether-a-go-go-related gene (HERG) channels: role of aromatic amino acids Y652 and F656. 2005, Pubmed
Siebrands, Structural requirements of human ether-a-go-go-related gene channels for block by bupivacaine. 2007, Pubmed , Xenbase
Smith, The inward rectification mechanism of the HERG cardiac potassium channel. 1996, Pubmed
Snyders, Structure and function of cardiac potassium channels. 1999, Pubmed
Spector, Class III antiarrhythmic drugs block HERG, a human cardiac delayed rectifier K+ channel. Open-channel block by methanesulfonanilides. 1996, Pubmed , Xenbase
Tester, Cardiomyopathic and channelopathic causes of sudden unexplained death in infants and children. 2009, Pubmed
Thomas, High-affinity blockade of human ether-a-go-go-related gene human cardiac potassium channels by the novel antiarrhythmic drug BRL-32872. 2001, Pubmed , Xenbase
Trott, AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. 2010, Pubmed
Trudeau, HERG, a human inward rectifier in the voltage-gated potassium channel family. 1995, Pubmed
Vandenberg, hERG K(+) channels: structure, function, and clinical significance. 2012, Pubmed
Wang, Modulation of HERG affinity for E-4031 by [K+]o and C-type inactivation. 1997, Pubmed , Xenbase
Wang, Single rat muscle Na+ channel mutation confers batrachotoxin autoresistance found in poison-dart frog Phyllobates terribilis. 2017, Pubmed
Wang, Cryo-EM Structure of the Open Human Ether-à-go-go-Related K+ Channel hERG. 2017, Pubmed
Wang, A quantitative analysis of the activation and inactivation kinetics of HERG expressed in Xenopus oocytes. 1997, Pubmed , Xenbase
Wang, Recent developments in computational prediction of HERG blockage. 2013, Pubmed
Warmke, A family of potassium channel genes related to eag in Drosophila and mammals. 1994, Pubmed
Weerapura, A comparison of currents carried by HERG, with and without coexpression of MiRP1, and the native rapid delayed rectifier current. Is MiRP1 the missing link? 2002, Pubmed , Xenbase
Whittaker, The Cyclin-dependent kinase inhibitor CYC202 (R-roscovitine) inhibits retinoblastoma protein phosphorylation, causes loss of Cyclin D1, and activates the mitogen-activated protein kinase pathway. 2004, Pubmed
Witchel, The low-potency, voltage-dependent HERG blocker propafenone--molecular determinants and drug trapping. 2004, Pubmed , Xenbase
Wu, Molecular Basis of Cardiac Delayed Rectifier Potassium Channel Function and Pharmacology. 2016, Pubmed
Yang, Extracellular potassium modulation of drug block of IKr. Implications for torsade de pointes and reverse use-dependence. 1996, Pubmed
Yarotskyy, Roscovitine binds to novel L-channel (CaV1.2) sites that separately affect activation and inactivation. 2010, Pubmed
Yarov-Yarovoy, Molecular determinants of voltage-dependent gating and binding of pore-blocking drugs in transmembrane segment IIIS6 of the Na(+) channel alpha subunit. 2001, Pubmed , Xenbase
Yazawa, Modeling Timothy syndrome with iPS cells. 2013, Pubmed
Zhang, Interactions between amiodarone and the hERG potassium channel pore determined with mutagenesis and in silico docking. 2016, Pubmed
Zhang, Amphiphilic blockers punch through a mutant CLC-0 pore. 2009, Pubmed
Zhou, Activation of human ether-a-go-go related gene (hERG) potassium channels by small molecules. 2011, Pubmed
Zhou, Properties of HERG channels stably expressed in HEK 293 cells studied at physiological temperature. 1998, Pubmed