Protein Phosphatase 2A Regulates Cardiac Na⁺ Channels.

Abstract

Voltage-gated Na⁺ channel ( I_Na) function is critical for normal cardiac excitability. However, the Na⁺ channel late component ( I_Na,L) is directly associated with potentially fatal forms of congenital and acquired human arrhythmia. CaMKII (Ca²⁺/calmodulin-dependent kinase II) enhances I_Na,L in response to increased adrenergic tone. However, the pathways that negatively regulate the CaMKII/Na_v1.5 axis are unknown and essential for the design of new therapies to regulate the pathogenic I_Na,L. To define phosphatase pathways that regulate I_Na,L in vivo. 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 I_Na,L regulation that was confirmed by direct I_Na,L recordings from B56α KO myocytes. Further, B56α KO myocytes display decreased sensitivity to isoproterenol-induced induction of arrhythmogenic I_Na,L, and reduced CaMKII-dependent phosphorylation of Na_v1.5. At the molecular level, PP2A/B56α complex was found to localize and coimmunoprecipitate with the primary cardiac Na_v channel, Na_v1.5. PP2A regulates Na_v1.5 activity in mouse cardiomyocytes. This regulation is critical for pathogenic Na_v1.5 late current and requires PP2A-B56α. Our study supports B56α as a novel target for the treatment of arrhythmia.