Issue

Vol. 65 No. 7: Issue 7

The undersigned hereby assign all rights, included but not limited to copyright, for this manuscript to CMB Association upon its submission for consideration to publication on Cellular and Molecular Biology. The rights assigned include, but are not limited to, the sole and exclusive rights to license, sell, subsequently assign, derive, distribute, display and reproduce this manuscript, in whole or in part, in any format, electronic or otherwise, including those in existence at the time this agreement was signed. The authors hereby warrant that they have not granted or assigned, and shall not grant or assign, the aforementioned rights to any other person, firm, organization, or other entity. All rights are automatically restored to authors if this manuscript is not accepted for publication.

β-Arrestin2 regulates the rapid component of delayed rectifier K+ currents and cardiac action potential of guinea pig cardiomyocytes after adrenergic stimulation

https://doi.org/10.14715/cmb/2019.65.7.23
Erdan Shi
Department of Cardiology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
Xiaozhu Zhou
Department of Cardiology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
Dongcheng Li
Department of Cardiology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
Yuzhen Zhang
Department of Cardiology, the First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215006, China
Jiamin Yuan
Department of Cardiology, the First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215006, China
Jiangang Zou
Department of Cardiology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China

Corresponding Author(s) : Erdan Shi

shierdan_njmu@163.com

Cellular and Molecular Biology, Vol. 65 No. 7: Issue 7

Abstract

A decrease in the rapid component of delayed rectifier potassium current (IKr) during chronic heart failure (CHF) prolongs action potential (AP), and plays a key role in the pathogenesis of ventricular arrhythmias. β-Arrestin2 has been shown to restore the inotropic reserve of β-adrenergic regulation, but little or nothing is known about its effect on intrinsic channel. This study investigated the role of β-arrestin2 in the regulation of cardiac hERG/IKr potassium channel and AP during chronic adrenergic stimulation. Single left ventricular myocytes were isolated from guinea pig heart, and were transfected with adenovirus encoding β-arrestin2, or β-arrestin2 siRNA or an empty adenovirus. Cell cultures containing 10 nM isoproterenol, 1 nM phenylephrine or vehicle alone (control medium) were electro-physiologically examined after 48 h of incubation. Action potential duration at 50 and 90 % of repolarization (APD50 and APD90) were measured using whole-cell patch-clamp recording. Sustained adrenergic stimulation significantly reduced the density of the IKr current (p < 0.001). β-Arrestin2 expression in cell cultures treated with isoproterenol or phenylephrine was significantly downregulated after adrenergic stimulation (p < 0.001). Overexpression of β-arrestin2 significantly attenuated isoproterenol or phenylephrine-induced reduction in IKr current. It also prevented the phenylephrine-induced prolongation of AP (p < 0.05 for APD50 and p < 0.001 for APD90), but did not significantly affect AP profile after exposure of the cardiomyocytes to isoproterenol (p > 0.05). Therefore, Increased levels of β-Arrestin2 weaken dysregulation of IKr current and prevent excessive AP prolongation, making it an effective anti-arrhythmic strategy.

Keywords

β-Arrestin2 Adrenergic stimulation Ventricular arrhythmias Action potential Potassium channel.
Shi, E., Zhou, X., Li, D., Zhang, Y., Yuan, J., & Zou, J. (2019). β-Arrestin2 regulates the rapid component of delayed rectifier K+ currents and cardiac action potential of guinea pig cardiomyocytes after adrenergic stimulation. Cellular and Molecular Biology, 65(7), 132–137. https://doi.org/10.14715/cmb/2019.65.7.23
Download Citation
Endnote/Zotero/Mendeley (RIS)
BibTeX
References
  1. Sanguinetti M.C., Jiang C., Curran M.E., Keating M.T. A mechanistic link between an inherited and an acquird cardiac arrthytmia: HERG encodes the IKr potassium channel. Cell. 1995; 81 (2): 299 – 307.
  2. Trudeau M.C., Warmke J.W., Ganetzky B., Robertson G.A. HERG, a human inward rectifier in the voltage-gated potassium channel family. Science. 1995; 269 (5220): 92 – 95.
  3. Curran M.E., Splawski I., Timothy K.W., Vincen G.M., Green E.D., Keating M.T. A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome. Cell. 1995; 80 (5): 795 – 803.
  4. Keating M.T., Sanguinetti M.C. Molecular and cellular mechanisms of cardiac arrhythmias. Cell. 2001; 104 (4): 569 – 580.
  5. Kuryshev Y.A. Pentamidine-Induced Long QT Syndrome and Block of hERG Trafficking. J. Pharmacol. Exp. Ther. 2004; 312 (1): 316 – 323.
  6. Zankov D.P., Yoshida H., Tsuji K., Toyoda F., Ding W.G., Matsuura H., Horie M. Adrenergic regulation of the rapid component of delayed rectifier K+ current: Implications for arrhythmogenesis in LQT2 patients. Hear. Rhythm. 2009; 6: 1038 – 1046.
  7. Karle C.A., Zitron E., Zhang W., Kathöfer S., Schoels W., Kiehn J. Rapid component I (Kr) of the guinea-pig cardiac delayed rectifier K(+) current is inhibited by beta(1)-adrenoreceptor activation, via cAMP/protein kinase A-dependent pathways. Cardiovasc. Res. 2002; 53 (2): 355 – 362.
  8. Bian J-S., Kagan A., McDonald T.V. Molecular analysis of PIP 2 regulation of HERG and I Kr. Am. J. Physiol. Circ. Physiol. 2004; 287 (5): H2154 – H2163.
  9. Patel P.A., Tilley D.G., Rockman H.A. Physiologic and cardiac roles of β-arrestins. J. Mol. Cell. Cardiol. 2009; 46 (3): 300 – 308.
  10. Nuber S., Zabel U., Lorenz K., Nuber A., Milligan G., Tobin A.B., Lohse M.J., Hoffmann C. β-Arrestin biosensors reveal a rapid, receptor-dependent activation/deactivation cycle. Nature. 2016; 531 (7596): 661 – 664.
  11. Zhabyeyev P., Zhang H., Oudit G.Y. Is β-Arrestin 2 a Magic Bullet for Heart Failure Treatment?, Hypertension. 2017; 70 (5): 887 – 889.
  12. Sangoi M.G., Lamothe S.M., Guo J., Yang T., Li W., Avery E.G., Fisher J.T., Zhang S. β-Arrestin-Mediated Regulation of the Human-Related Gene Potassium Channel. Mol. Pharmacl. 2017; 92:
  13. Wang H., Chen Y., Zhu H., Wang S., Zhang X., Xu D., Cao K., Zou J. Increased Response to β2-Adrenoreceptor Stimulation Augments Inhibition of IKr in Heart Failure Ventricular Myocytes. PLoS One. 2012; 7 (9): e46186.
  14. Dong D-L., Liu Y., Zhou Y-H., Song W-H., Wang H., Yang B-F. Decreases of voltage-dependent K+ currents densities in ventricular myocytes of guinea pigs by chronic oxidant stress. Acta Pharmacol. Sin. 2004; 25 (6): 751 – 755.
  15. Wang Y., Yuan J., Qian Z., Zhang X., Chen Y., Hou X., Zou J. β2 adrenergic receptor activation governs cardiac repolarization and arrhythmogenesis in a Guinea pig model of heart failure. Sci. Rep. 2015; 5: 7681.
  16. McCrink K.A., Maning J., Vu A., Jafferjee M., Marrero C., Brill A., Bathgate-Siryk A., Dabul S., Koch W.J. A. Lymperopoulos, β-Arrestin2 Improves Post-Myocardial Infarction Heart Failure via Sarco(endo)plasmic Reticulum Ca2+-ATPase-Dependent Positive Inotropy in Cardiomyocytes. Hypertension. 2017;
  17. Thomas D., Karle C., Kiehn J. The Cardiac hERG/IKr Potassium Channel as Pharmacological Target: Structure, Function, Regulation, and Clinical Applications. Curr. Pharm. Des. 2006; 12 (18): 2271 – 2283.
  18. Banyasz T., Jian Z., Horvath B., Khabbaz S., Izu L.T., Chen-Izu Y. Beta-adrenergic stimulation reverses the I Kr–I Ks dominant pattern during cardiac action potential. Pflugers Arch. Eur. J. Physiol. 2014; 466 (11): 2067 – 2076.
  19. Zhang L-M., Wang Z., Nattel S. Effects of sustained β-adrenergic stimulation on ionic currents of cultured adult guinea pig cardiomyocytes. Am. J. Physiol. Circ. Physiol. 2002; 282 (3): H880 – 889.
  20. Jiang M., Dun W., Fan J-S., Tseng G-N. Use-dependent "agonist” effect of azimilide on the HERG channel. J. Pharmacol. Exp. Ther. 1999; 291 (3): 1324 – 1336.
  21. Wang S., Xu D-J., Cai J-B., Huang Y-Z., Zou J-G., Cao K-J. Rapid component I(Kr) of cardiac delayed rectifier potassium currents in guinea-pig is inhibited by alpha(1)-adrenoreceptor activation via protein kinase A and protein kinase C-dependent pathways. Eur. J. Pharmacol. 2009; 608 (1 – 3): 1 – 6.
  22. Hegyi B., Bossuyt J., Ginsburg K.S.,. Mendoza L.M, Talken L., Ferrier W.T., Pogwizd S.M., Izu L.T., Chen-Izu Y., Bers D.M. Altered Repolarization Reserve in Failing Rabbit Ventricular Myocytes: Calcium and β-Adrenergic Effects on Delayed- and Inward-Rectifier Potassium Currents. Circ. Arrhythmia Electrophysiol. 2018; 11 (2): e005852.
  23. Ryba D.M., Li J., Cowan C.L., Russell B., Wolska B.M., John-Solaro R. Long-Term Biased β-Arrestin Signaling Improves Cardiac Structure and Function in Dilated Cardiomyopathy. Circulation. 2017; 135 (11): 1056 – 1070.
  24. í…gren R., í…rhem P., Nilsson J., Sahlholm K. The Beta-Arrestin-Biased Dopamine D2 Receptor Ligand, UNC9994, Is a Partial Agonist at G-Protein-Mediated Potassium Channel Activation. Int. J. Neuropsychopharmacol. 2018; 21 (12): 1102 – 1108.
  25. Li G.R., Lau C.P, Leung T.K., Nattel S. Ionic current abnormalities associated with prolonged action potentials in cardiomyocytes from diseased human right ventricles. Hear. Rhythm. 2004; 1: 460 – 468.
  26. Li G-R., Lau C-P., Ducharme A., Tardif J-C., Nattel S. Transmural action potential and ionic current remodeling in ventricles of failing canine hearts. Am. J. Physiol. Circ. Physiol. 2002; 283 (3): H1031 – 1041.
  27. Sanguinetti M.C., Tristani-Firouzi M. hERG potassium channels and cardiac arrhythmia. Nature. 2006; 440 (7083): 463 – 469.
  28. Flores N.A., Sheridan D.J. Electrophysiological effects of alpha-adrenoceptor stimulation in perfused and superfused myocardium. J. Mol. Cell. Cardiol. 1991; 23 (8): 973 – 985.
  29. Qin M., Liu T., Hu H., Wang T., Yu S., Huang C. Effect of isoprenaline chronic stimulation on APD restitution and ventricular arrhythmogenesis. J. Cardiol. 2013; 61 (2): 162 – 168.
  30. Goldhaber J.I., Xie L.H., Duong T., Motter C., Khuu K., Weiss J.N. Action potential duration restitution and alternans in rabbit ventricular myocytes: The key role of intracellular calcium cycling. Circ. Res. 2005; 96 (4): 459 – 466.
  31. Saucerman J.J., McCulloch A.D. Cardiac β-adrenergic signaling: From subcellular microdomains to heart failure. Ann. N. Y. Acad. Sci. 2006; 1080: 348 – 361.
  32. Szentandrássy N., Farkas V., Bárándi L., B. Hegyi, F. Ruzsnavszky, B. Horváth, T. Bányász, J. Magyar, I. Márton, P.P. Nánási, Role of action potential configuration and the contribution of Ca 2+ and K+ currents to isoprenaline-induced changes in canine ventricular cells. Br. J. Pharmacol. 2012; 167 (3): 599 – 611.
  33. Zaza A., Rocchetti M., Brioschi A., Cantadori A., Ferroni A. Dynamic Ca2+-induced inward rectification of K+ current during the ventricular action potential. Circ. Res. 1998; 82 (9): 947 – 956.
  34. Johnson D.M., Heijman J., Bode E.F. Greensmith D.J., VanDerLinde H., Abi-Gerges N., Eisner D.A., Trafford A.W., Volders P.G.A. Diastolic spontaneous calcium release from the sarcoplasmic reticulum increases beat-to-beat variability of repolarization in canine ventricular myocytes after β-adrenergic stimulation. Circ. Res. 2013; 112 (2): 246 – 256.
Read More
Author biographies is not available.
Crossref
Scopus
Google Scholar
Europe PMC
Download this PDF file
PDF SUPPLEMENTARY FILE
Statistic
Read Counter : 857 Download : 416