IDEAS home Printed from https://ideas.repec.org/a/plo/pone00/0181823.html
   My bibliography  Save this article

Inhibitory effects and mechanism of dihydroberberine on hERG channels expressed in HEK293 cells

Author

Listed:
  • Dahai Yu
  • Lin Lv
  • Li Fang
  • Bo Zhang
  • Junnan Wang
  • Ge Zhan
  • Lei Zhao
  • Xin Zhao
  • Baoxin Li

Abstract

The human ether-a-go-go-related gene (hERG) potassium channel conducts rapid delayed rectifier potassium currents (IKr) and contributes to phase III cardiac action potential repolarization. Drugs inhibit hERG channels by binding to aromatic residues in hERG helixes. Berberine (BBR) has multiple actions, and its hydrogenated derivative dihydroberberine (DHB) is a potential candidate for developing new drugs. Previous studies have demonstrated that BBR blocks hERG channels and prolongs action potential duration (APD). Our present study aimed to investigate the effects and mechanism of DHB on hERG channels. Protein expression and the hERG current were analyzed using western blotting and patch-clamp, respectively. DHB inhibited the hERG current concentration-dependently after instantaneous perfusion, accelerated channel inactivation by directly binding tyrosine (Tyr652) and phenylalanine (Phe656), and decreased mature (155-kDa) and simultaneously increased immature (135-kDa) hERG expression, respectively. This suggests disruption of forward trafficking of hERG channels. Besides, DHB remarkably reduced heat shock protein 90 (Hsp90) expression and its interaction with hERG, indicating that DHB disrupted hERG trafficking by impairing channel folding. Meanwhie, DHB enhanced the expression of cleaved activating transcription factor-6 (ATF-6), a biomarker of unfolded protein response (UPR). Expression of calnexin and calreticulin, chaperones activated by ATF-6 to facilitate channel folding, were also increased, which indicating UPR activation. Additionally, the degradation rate of mature 155-kDa hERG increased following DHB exposure. In conclusion, we demonstrated that DHB acutely blocked hERG channels by binding the aromatic Tyr652 and Phe656. DHB may decrease hERG plasma membrane expression through two pathways involving disruption of forward trafficking of immature hERG channels and enhanced degradation of mature hERG channels. Furthermore, forward trafficking was disrupted by impaired channel folding associated with altered interactions between hERG proteins and chaperones. Finally, trafficking inhibition activated UPR, and mature hERG channel degradation was increased by DHB.

Suggested Citation

  • Dahai Yu & Lin Lv & Li Fang & Bo Zhang & Junnan Wang & Ge Zhan & Lei Zhao & Xin Zhao & Baoxin Li, 2017. "Inhibitory effects and mechanism of dihydroberberine on hERG channels expressed in HEK293 cells," PLOS ONE, Public Library of Science, vol. 12(8), pages 1-19, August.
  • Handle: RePEc:plo:pone00:0181823
    DOI: 10.1371/journal.pone.0181823
    as

    Download full text from publisher

    File URL: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0181823
    Download Restriction: no

    File URL: https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0181823&type=printable
    Download Restriction: no

    File URL: https://libkey.io/10.1371/journal.pone.0181823?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Michael C. Sanguinetti & Martin Tristani-Firouzi, 2006. "hERG potassium channels and cardiac arrhythmia," Nature, Nature, vol. 440(7083), pages 463-469, March.
    2. F. Ulrich Hartl & Andreas Bracher & Manajit Hayer-Hartl, 2011. "Molecular chaperones in protein folding and proteostasis," Nature, Nature, vol. 475(7356), pages 324-332, July.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Erik B Nordquist & Charles A English & Eugenia M Clerico & Woody Sherman & Lila M Gierasch & Jianhan Chen, 2021. "Physics-based modeling provides predictive understanding of selectively promiscuous substrate binding by Hsp70 chaperones," PLOS Computational Biology, Public Library of Science, vol. 17(11), pages 1-24, November.
    2. Amrita X Sarkar & Eric A Sobie, 2010. "Regression Analysis for Constraining Free Parameters in Electrophysiological Models of Cardiac Cells," PLOS Computational Biology, Public Library of Science, vol. 6(9), pages 1-11, September.
    3. Franke, R., 2016. "CHIMERA: Top-down model for hierarchical, overlapping and directed cluster structures in directed and weighted complex networks," Physica A: Statistical Mechanics and its Applications, Elsevier, vol. 461(C), pages 384-408.
    4. Verena Kohler & Andreas Kohler & Lisa Larsson Berglund & Xinxin Hao & Sarah Gersing & Axel Imhof & Thomas Nyström & Johanna L. Höög & Martin Ott & Claes Andréasson & Sabrina Büttner, 2024. "Nuclear Hsp104 safeguards the dormant translation machinery during quiescence," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    5. Matthias M. Schneider & Saurabh Gautam & Therese W. Herling & Ewa Andrzejewska & Georg Krainer & Alyssa M. Miller & Victoria A. Trinkaus & Quentin A. E. Peter & Francesco Simone Ruggeri & Michele Vend, 2021. "The Hsc70 disaggregation machinery removes monomer units directly from α-synuclein fibril ends," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
    6. Il-Soo Park & Seongchan Kim & Yeajee Yim & Ginam Park & Jinahn Choi & Cheolhee Won & Dal-Hee Min, 2022. "Multifunctional synthetic nano-chaperone for peptide folding and intracellular delivery," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    7. Maru Jaime-Garza & Carlos A. Nowotny & Daniel Coutandin & Feng Wang & Mariano Tabios & David A. Agard, 2023. "Hsp90 provides a platform for kinase dephosphorylation by PP5," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    8. Krishna B. S. Swamy & Hsin-Yi Lee & Carmina Ladra & Chien-Fu Jeff Liu & Jung-Chi Chao & Yi-Yun Chen & Jun-Yi Leu, 2022. "Proteotoxicity caused by perturbed protein complexes underlies hybrid incompatibility in yeast," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    9. Jaime Carrasco & Rosa Antón & Alejandro Valbuena & David Pantoja-Uceda & Mayur Mukhi & Rubén Hervás & Douglas V. Laurents & María Gasset & Javier Oroz, 2023. "Metamorphism in TDP-43 prion-like domain determines chaperone recognition," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    10. Martin Grønbæk-Thygesen & Vasileios Voutsinos & Kristoffer E. Johansson & Thea K. Schulze & Matteo Cagiada & Line Pedersen & Lene Clausen & Snehal Nariya & Rachel L. Powell & Amelie Stein & Douglas M., 2024. "Deep mutational scanning reveals a correlation between degradation and toxicity of thousands of aspartoacylase variants," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    11. Fang Du & Joseph J Babcock & Haibo Yu & Beiyan Zou & Min Li, 2015. "Global Analysis Reveals Families of Chemical Motifs Enriched for hERG Inhibitors," PLOS ONE, Public Library of Science, vol. 10(2), pages 1-21, February.
    12. Joshua Mayourian & Ruben M Savizky & Eric A Sobie & Kevin D Costa, 2016. "Modeling Electrophysiological Coupling and Fusion between Human Mesenchymal Stem Cells and Cardiomyocytes," PLOS Computational Biology, Public Library of Science, vol. 12(7), pages 1-29, July.
    13. Pengfei Xu & Joy C. Yang & Bo Chen & Shu Ning & Xiong Zhang & Leyi Wang & Christopher Nip & Yuqiu Shen & Oleta T. Johnson & Gabriela Grigorean & Brett Phinney & Liangren Liu & Qiang Wei & Eva Corey & , 2024. "Proteostasis perturbation of N-Myc leveraging HSP70 mediated protein turnover improves treatment of neuroendocrine prostate cancer," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    14. Bryan Cernuda & Christopher Thomas Fernandes & Salma Mohamed Allam & Matthew Orzillo & Gabrielle Suppa & Zuleen Chia Chang & Demosthenes Athanasopoulos & Zafir Buraei, 2019. "The molecular determinants of R-roscovitine block of hERG channels," PLOS ONE, Public Library of Science, vol. 14(9), pages 1-26, September.
    15. Haiyan Mao & Xiaoli Lu & Justin Michael Karush & Xiaoyan Huang & Xi Yang & Yanna Ba & Ying Wang & Ningsheng Liu & Jianqing Zhou & Jiangfang Lian, 2013. "Pharmacologic Approach to Defective Protein Trafficking in the E637K-hERG Mutant with PD-118057 and Thapsigargin," PLOS ONE, Public Library of Science, vol. 8(6), pages 1-12, June.
    16. Moniruzzaman & Mohammed Jabedul Hoque & Amrin Ahsan & Md Belayet Hossain, 2018. "Molecular Docking, Pharmacokinetic, and DFT Calculation of Naproxen and its Degradants," Biomedical Journal of Scientific & Technical Research, Biomedical Research Network+, LLC, vol. 9(5), pages 7360-7365, October.
    17. Emelie E. Aspholm & Jens Lidman & Björn M. Burmann, 2024. "Structural basis of substrate recognition and allosteric activation of the proapoptotic mitochondrial HtrA2 protease," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    18. Hyunju Cho & Yumeng Liu & SangYoon Chung & Sowmya Chandrasekar & Shimon Weiss & Shu-ou Shan, 2024. "Dynamic stability of Sgt2 enables selective and privileged client handover in a chaperone triad," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    19. Guosheng Chen & Linjing Tong & Siming Huang & Shuyao Huang & Fang Zhu & Gangfeng Ouyang, 2022. "Hydrogen-bonded organic framework biomimetic entrapment allowing non-native biocatalytic activity in enzyme," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    20. Verena Rukes & Mathieu E. Rebeaud & Louis W. Perrin & Paolo De Los Rios & Chan Cao, 2024. "Single-molecule evidence of Entropic Pulling by Hsp70 chaperones," Nature Communications, Nature, vol. 15(1), pages 1-8, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:plo:pone00:0181823. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: plosone (email available below). General contact details of provider: https://journals.plos.org/plosone/ .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.