Mona El Refaey1,2, Hassan Musa1,2, Nathaniel P Murphy1,2, Ellen R Lubbers1,2, Michel Skaf1,2, Mei Han1,2, Omer Cavus1,2, Sara N Koenig1,2, Michael J Wallace1,2, Daniel Gratz1,3, Elisa Bradley1,4, Katherina M Alsina5,6,7, Xander H T Wehrens8, Thomas J Hund1,4,3, Peter J Mohler1,4,2. 1. From the Ohio State University College of Medicine and Wexner Medical Center, The Frick Center for Heart Failure and Arrhythmia, The Dorothy M. Davis Heart and Lung Research Institute, Columbus (M.E.R., H.M., N.P.M., E.R.L., M.S., M.H., O.C., S.N.K., M.J.W., D.G., E.B., T.J.H., P.J.M.). 2. Department of Physiology and Cell Biology, Ohio State University, Columbus (M.E.R., H.M., N.P.M., E.R.L., M.S., M.H., O.C., S.N.K., M.J.W., P.J.M.). 3. Department of Biomedical Engineering, Ohio State University College of Engineering, Columbus (D.G., T.J.H.). 4. Department of Internal Medicine, Ohio State University College of Medicine, Columbus (E.B., T.J.H., P.J.M.). 5. Department of Molecular Physiology and Biophysics (K.M.A.), Baylor College of Medicine, Houston, TX. 6. Division of Cardiology, Department of Medicine (K.M.A.), Baylor College of Medicine, Houston, TX. 7. Division of Cardiology, Department of Pediatrics (K.M.A.), Baylor College of Medicine, Houston, TX. 8. Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX (X.H.T.W.).
Abstract
RATIONALE: Voltage-gated Na+ channel ( INa) function is critical for normal cardiac excitability. However, the Na+ channel late component ( INa,L) is directly associated with potentially fatal forms of congenital and acquired human arrhythmia. CaMKII (Ca2+/calmodulin-dependent kinase II) enhances INa,L in response to increased adrenergic tone. However, the pathways that negatively regulate the CaMKII/Nav1.5 axis are unknown and essential for the design of new therapies to regulate the pathogenic INa,L. OBJECTIVE: To define phosphatase pathways that regulate INa,L in vivo. METHODS AND RESULTS: A mouse model lacking a key regulatory subunit (B56α) of the PP (protein phosphatase) 2A holoenzyme displayed aberrant action potentials after adrenergic stimulation. Unbiased computational modeling of B56α KO (knockout) mouse myocyte action potentials revealed an unexpected role of PP2A in INa,L regulation that was confirmed by direct INa,L recordings from B56α KO myocytes. Further, B56α KO myocytes display decreased sensitivity to isoproterenol-induced induction of arrhythmogenic INa,L, and reduced CaMKII-dependent phosphorylation of Nav1.5. At the molecular level, PP2A/B56α complex was found to localize and coimmunoprecipitate with the primary cardiac Nav channel, Nav1.5. CONCLUSIONS: PP2A regulates Nav1.5 activity in mouse cardiomyocytes. This regulation is critical for pathogenic Nav1.5 late current and requires PP2A-B56α. Our study supports B56α as a novel target for the treatment of arrhythmia.
RATIONALE: Voltage-gated Na+ channel ( INa) function is critical for normal cardiac excitability. However, the Na+ channel late component ( INa,L) is directly associated with potentially fatal forms of congenital and acquired humanarrhythmia. CaMKII (Ca2+/calmodulin-dependent kinase II) enhances INa,L in response to increased adrenergic tone. However, the pathways that negatively regulate the CaMKII/Nav1.5 axis are unknown and essential for the design of new therapies to regulate the pathogenic INa,L. OBJECTIVE: To define phosphatase pathways that regulate INa,L in vivo. METHODS AND RESULTS: A mouse model lacking a key regulatory subunit (B56α) of the PP (protein phosphatase) 2A holoenzyme displayed aberrant action potentials after adrenergic stimulation. Unbiased computational modeling of B56α KO (knockout) mouse myocyte action potentials revealed an unexpected role of PP2A in INa,L regulation that was confirmed by direct INa,L recordings from B56α KO myocytes. Further, B56α KO myocytes display decreased sensitivity to isoproterenol-induced induction of arrhythmogenic INa,L, and reduced CaMKII-dependent phosphorylation of Nav1.5. At the molecular level, PP2A/B56α complex was found to localize and coimmunoprecipitate with the primary cardiac Nav channel, Nav1.5. CONCLUSIONS:PP2A regulates Nav1.5 activity in mouse cardiomyocytes. This regulation is critical for pathogenic Nav1.5 late current and requires PP2A-B56α. Our study supports B56α as a novel target for the treatment of arrhythmia.
Entities:
Keywords:
ankyrins; arrhythmias, cardiac; calcium-calmodulin-dependent protein kinase type 2; phosphorylation; physiology
Authors: Mona El Refaey; Hassan Musa; Sakima A Smith; Philip F Binkley; Elisa Bradley; Thomas J Hund; Peter J Mohler Journal: Circ Res Date: 2019-04-12 Impact factor: 17.367
Authors: Ellen R Lubbers; Nathaniel P Murphy; Hassan Musa; Claire Yu-Mei Huang; Rohan Gupta; Morgan V Price; Mei Han; Georges Daoud; Daniel Gratz; Mona El Refaey; Xianyao Xu; Nicole K Hoeflinger; Emma L Friel; Peter Lancione; Michael J Wallace; Omer Cavus; Samantha L Simmons; Jordan L Williams; Michel Skaf; Sara N Koenig; Paul M L Janssen; Matthew N Rasband; Thomas J Hund; Peter J Mohler Journal: J Biol Chem Date: 2019-05-07 Impact factor: 5.157
Authors: Amara Greer-Short; Hassan Musa; Katherina M Alsina; Li Ni; Tarah A Word; Julia O Reynolds; Daniel Gratz; Cemantha Lane; Mona El-Refaey; Sathya Unudurthi; Michel Skaf; Ning Li; Vadim V Fedorov; Xander H T Wehrens; Peter J Mohler; Thomas J Hund Journal: Heart Rhythm Date: 2019-10-14 Impact factor: 6.343
Authors: Iacopo Galleano; Hendrik Harms; Koushik Choudhury; Keith Khoo; Lucie Delemotte; Stephan Alexander Pless Journal: Proc Natl Acad Sci U S A Date: 2021-08-17 Impact factor: 11.205