Hexachlorophene Is a Potent KCNQ1/KCNE1 Potassium Channel Activator Which Rescues LQTs Mutants

Zheng, Yueming; Zhu, Xuejing; Zhou, Pingzheng; Lan, Xi; Xu, Haiyan; Li, Min; Gao, Zhaobing

doi:10.1371/journal.pone.0051820

Cited by 29 publications

(28 citation statements)

References 32 publications

(48 reference statements)

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“…However, there are reports, for example, suggesting that KCNEs affect other Kv channels, including Kv4.2 (41). It would also be interesting to determine whether the specificity for unsaturated KCNQ1/KCNE stoichiometry is in fact applicable to or different from that by other allosteric modulators (42,43), including ones discovered recently (12,44). The continuum of incremental subunit coassembly and that of differential pharmacological sensitivity to small-molecule modulators highlight both complexity of the regulation and opportunities to develop therapeutic interventions.…”

Section: Discussionmentioning

confidence: 99%

Dynamic subunit stoichiometry confers a progressive continuum of pharmacological sensitivity by KCNQ potassium channels

Lin

Mattmann

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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122

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Voltage-gated KCNQ1 (Kv7.1) potassium channels are expressed abundantly in heart but they are also found in multiple other tissues. Differential coassembly with single transmembrane KCNE beta subunits in different cell types gives rise to a variety of biophysical properties, hence endowing distinct physiological roles for KCNQ1-KCNEx complexes. Mutations in either KCNQ1 or KCNE1 genes result in diseases in brain, heart, and the respiratory system. In addition to complexities arising from existence of five KCNE subunits, KCNE1 to KCNE5, recent studies in heterologous systems suggest unorthodox stoichiometric dynamics in subunit assembly is dependent on KCNE expression levels. The resultant KCNQ1-KCNE channel complexes may have a range of zero to two or even up to four KCNE subunits coassembling per KCNQ1 tetramer. These findings underscore the need to assess the selectivity of small-molecule KCNQ1 modulators on these different assemblies. Here we report a unique small-molecule gating modulator, ML277, that potentiates both homomultimeric KCNQ1 channels and unsaturated heteromultimeric (KCNQ1) 4 (KCNE1) n (n < 4) channels. Progressive increase of KCNE1 or KCNE3 expression reduces efficacy of ML277 and eventually abolishes ML277-mediated augmentation. In cardiomyocytes, the slowly activating delayed rectifier potassium current, or I Ks , is believed to be a heteromultimeric combination of KCNQ1 and KCNE1, but it is not entirely clear whether I Ks is mediated by KCNE-saturated KCNQ1 channels or by channels with intermediate stoichiometries. We found ML277 effectively augments I Ks current of cultured human cardiomyocytes and shortens action potential duration. These data indicate that unsaturated heteromultimeric (KCNQ1) 4 (KCNE1) n channels are present as components of I Ks and are pharmacologically distinct from KCNE-saturated KCNQ1-KCNE1 channels.cardiac physiology | drug | long QT | pharmacology

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Section: Discussionmentioning

confidence: 99%

Dynamic subunit stoichiometry confers a progressive continuum of pharmacological sensitivity by KCNQ potassium channels

Lin

Mattmann

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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122

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“…A combined approach of electrophysiology and molecular dynamic simulation indicated that ML277 binds to the side pockets between adjacent KCNQ1 subunits to allosterically modify channel gating 94 . Nonspecific compounds such as the chloride channel blockers mefenamic acid and DIDS, and the anti-bacterial hexachlorophene can also activate I Ks , but these compounds exert stronger potentiation on KCNQ1/KCNE1 channels than on homomeric KCNQ1 channels 96,97 . Unlike other KCNQ1 channel activators, the negative shift of voltage dependence of channel activation produced by phenylboronic acid is independent of KCNE1 subunits 98 .…”

Section: Molecular Pharmacology Of Cardiac Delayed Rectifier K+ Channelsmentioning

confidence: 99%

Molecular Basis of Cardiac Delayed Rectifier Potassium Channel Function and Pharmacology

Sanguinetti

2016

Cardiac Electrophysiology Clinics

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Synopsis Human cardiomyocytes express three distinct types of delayed rectifier potassium channels. hERG1 channels conduct the rapidly activating current IKr, KCNQ1/KCNE1 channels conduct the slowly activating current IKs, and Kv1.5 channels conduct an ultrarapid activating current IKur. Here we provide a general overview of the mechanistic and structural basis of ion selectivity, gating and pharmacology of the three types of cardiac delayed rectifier K+ channels. Most blockers bind to S6 residues that line the central cavity of the channel, whereas activators interact with the channel at four symmetrical binding sites outside the cavity.

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“…However, one Kv7.1 mutation is reported to disrupt R-L3 binding and, thereby, channel activation [20]. Recently, further Kv7.1 activators have been described [22][23][24][25]. Potent activators of Kv7.4 include BMS-204352 [26], but often lack selectivity.…”

Section: Introductionmentioning

confidence: 99%

The Natural Plant Product Rottlerin Activates Kv7.1/KCNE1 Channels

Matschke

Piccini²,

Schubert

et al. 2016

Cell Physiol Biochem

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Background/Aims: Acquired as well as inherited channelopathies are disorders that are caused by altered ion channel function. A family of channels whose malfunction is associated with different channelopathies is the Kv7 K⁺ channel family; and restoration of normal Kv7 channel function by small molecule modulators is a promising approach for treatment of these often fatal diseases. Methods: Here, we show the modulation of Kv7 channels by the natural compound Rottlerin heterologously expressed in Xenopus laevis oocytes and on iPSC cardiomyocytes overexpressing Kv7.1 channels. Results: We show that currents carried by Kv7.1 (EC₅₀ = 1.48 μM), Kv7.1/KCNE1 (EC₅₀ = 4.9 μM), and Kv7.4 (EC₅₀ = 0.148 μM) are strongly enhanced by the compound, whereas Kv7.2, Kv7.2/Kv7.3, and Kv7.5 are not sensitive to Rottlerin. Studies on Kv7.1/KCNE1 mutants and in silico modelling indicate that Rottlerin binds to the R-L3-activator site. Rottlerin mediated activation of Kv7.1/KCNE1 channels might be a promising approach in long QT syndrome. As a proof of concept, we show that Rottlerin shortens cardiac repolarisation in iPSC-derived cardiomyocytes expressing Kv7.1.Conclusion: Rottlerin or an optimized derivative holds a potential as QT interval correcting drug.

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Hexachlorophene Is a Potent KCNQ1/KCNE1 Potassium Channel Activator Which Rescues LQTs Mutants

Cited by 29 publications

References 32 publications

Dynamic subunit stoichiometry confers a progressive continuum of pharmacological sensitivity by KCNQ potassium channels

Dynamic subunit stoichiometry confers a progressive continuum of pharmacological sensitivity by KCNQ potassium channels

Molecular Basis of Cardiac Delayed Rectifier Potassium Channel Function and Pharmacology

The Natural Plant Product Rottlerin Activates Kv7.1/KCNE1 Channels

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