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Auxiliary subunits control biophysical properties and response to compound NS5806 of the Kv4 potassium channel complex.


ABSTRACT: Kv4 pore-forming subunits co-assemble with ?-subunits including KChIP2 and DPP6 and the resultant complexes conduct cardiac transient outward K+ current (Ito). Compound NS5806 has been shown to potentate Ito in canine cardiomyocytes; however, its effects on Ito in other species yet to be determined. We found that NS5806 inhibited native Ito in a concentration-dependent manner (0.1~30 ?M) in both mouse ventricular cardiomyocytes and human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), but potentiated Ito in the canine cardiomyocytes. In HEK293 cells co-transfected with cloned Kv4.3 (or Kv4.2) and ?-subunit KChIP2, NS5806 significantly increased the peak current amplitude and slowed the inactivation. In contrast, NS5806 suppressed the current and accelerated inactivation of the channels when cells were co-transfected with Kv4.3 (or Kv4.2), KChIP2 and another ?-subunit, DPP6-L (long isoform). Western blot analysis showed that DPP6-L was dominantly expressed in both mouse ventricular myocardium and hiPSC-CMs, while it was almost undetectable in canine ventricular myocardium. In addition, low level of DPP6-S expression was found in canine heart, whereas levels of KChIP2 expression were comparable among all three species. siRNA knockdown of DPP6 antagonized the Ito inhibition by NS5806 in hiPSC-CMs. Molecular docking simulation suggested that DPP6-L may associate with KChIP2 subunits. Mutations of putative KChIP2-interacting residues of DPP6-L reversed the inhibitory effect of NS5806 into potentiation of the current. We conclude that a pharmacological modulator can elicit opposite regulatory effects on Kv4 channel complex among different species, depending on the presence of distinct ?-subunits. These findings provide novel insight into the molecular design and regulation of cardiac Ito. Since Ito is a potential therapeutic target for treatment of multiple cardiovascular diseases, our data will facilitate the development of new therapeutic Ito modulators.

SUBMITTER: Zhang H 

PROVIDER: S-EPMC6972550 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Auxiliary subunits control biophysical properties and response to compound NS5806 of the Kv4 potassium channel complex.

Zhang Hongxue H   Zhang Hua H   Wang Chanjuan C   Wang Yuhong Y   Zou Ruya R   Shi Chenxia C   Guan Bingcai B   Gamper Nikita N   Xu Yanfang Y  

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20191127 1


Kv4 pore-forming subunits co-assemble with β-subunits including KChIP2 and DPP6 and the resultant complexes conduct cardiac transient outward K<sup>+</sup> current (I<sub>to</sub>). Compound NS5806 has been shown to potentate I<sub>to</sub> in canine cardiomyocytes; however, its effects on I<sub>to</sub> in other species yet to be determined. We found that NS5806 inhibited native I<sub>to</sub> in a concentration-dependent manner (0.1~30 μM) in both mouse ventricular cardiomyocytes and human-ind  ...[more]

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