Protein Phosphatase 2A Regulates Cardiac Na+ Channels

Mona El Refaey, Hassan Musa, Nathaniel P. Murphy, Ellen R. Lubbers, Michel Skaf, Mei Han, Omer Cavus, Sara N. Koenig, Michael J. Wallace, Daniel Gratz, Elisa Bradley, Katherina M. Alsina, Xander H.T. Wehrens, Thomas J. Hund, Peter J. Mohler

Research output: Contribution to journalArticlepeer-review

18 Citations (SciVal)

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.

Original languageEnglish (US)
Pages (from-to)737-746
Number of pages10
JournalCirculation research
Volume124
Issue number5
DOIs
StatePublished - Mar 1 2019

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cardiology and Cardiovascular Medicine

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