期刊
CIRCULATION RESEARCH
卷 124, 期 5, 页码 737-746出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCRESAHA.118.314350
关键词
ankyrins; arrhythmias, cardiac; calcium-calmodulin-dependent protein kinase type 2; phosphorylation; physiology
资金
- NIH [HL135754, HL134824, HL139348, HL135096, HL114383, HL114893, HL089598, HL091947, HL117641, HL137325, HL137331]
- Ohio State JB Project
Rationale: Voltage-gated Na+ channel (I-Na) function is critical for normal cardiac excitability. However, the Na+ channel late component (I-Na,I-L) is directly associated with potentially fatal forms of congenital and acquired human arrhythmia. CaMKII (Ca2+/calmodulin-dependent kinase II) enhances I-Na,I-L in response to increased adrenergic tone. However, the pathways that negatively regulate the CaMKII/Na(v)1.5 axis are unknown and essential for the design of new therapies to regulate the pathogenic I-Na,I-L. Objective: To define phosphatase pathways that regulate I-Na,I-L in vivo. Methods and Results: A mouse model lacking a key regulatory subunit (B56a) of the PP (protein phosphatase) 2A holoenzyme displayed aberrant action potentials after adrenergic stimulation. Unbiased computational modeling of B56a KO (knockout) mouse myocyte action potentials revealed an unexpected role of PP2A in I-Na,I-L regulation that was confirmed by direct I-Na,I-L recordings from B56a KO myocytes. Further, B56a KO myocytes display decreased sensitivity to isoproterenol-induced induction of arrhythmogenic I-Na,I-L, and reduced CaMKIIdependent phosphorylation of Na(v)1.5. At the molecular level, PP2A/B56a complex was found to localize and coimmunoprecipitate with the primary cardiac Na v channel, Na(v)1.5. Conclusions: PP2A regulates Na(v)1.5 activity in mouse cardiomyocytes. This regulation is critical for pathogenic Na(v)1.5 late current and requires PP2A-B56a. Our study supports B56a as a novel target for the treatment of arrhythmia.
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