Zhang, H, Zhang, H, Wang, C et al. (6 more authors) (2020) Auxiliary subunits control biophysical properties and response to compound NS5806 of the Kv4 potassium channel complex. The FASEB Journal, 34 (1). pp. 807-821. ISSN 0892-6638
Abstract
Kv4 pore‐forming subunits co‐assemble with β‐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 μM) 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 β‐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 β‐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 β‐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.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2019 The Authors. The FASEB Journal published by Wiley Periodicals, Inc. on behalf of Federation of American Societies for Experimental Biology. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
Keywords: | cardiomyocyte; dipeptidyl peptidase‐like protein; K+ channel‐interacting protein; transient outward K+ current |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Biomedical Sciences (Leeds) |
Funding Information: | Funder Grant number BBSRC BB/R003068/1 BBSRC BB/R02104X/1 |
Depositing User: | Symplectic Publications |
Date Deposited: | 14 Nov 2019 15:29 |
Last Modified: | 29 Jan 2020 14:50 |
Status: | Published |
Publisher: | Wiley |
Identification Number: | 10.1096/fj.201902010RR |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:153435 |