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- Title
Protein phosphatase 2A regulatory subunit B56α limits phosphatase activity in the heart.
- Authors
Little, Sean C.; Curran, Jerry; Makara, Michael A.; Kline, Crystal F.; Hsiang-Ting Ho; Zhaobin Xu; Xiangqiong Wu; Polina, Iuliia; Musa, Hassan; Meadows, Allison M.; Carnes, Cynthia A.; Biesiadecki, Brandon J.; Davis, Jonathan P.; Weisleder, Noah; Györke, Sandor; Wehrens, Xander H.; Hund, Thomas J.; Mohler, Peter J.
- Abstract
Protein phosphatase 2A (PP2A) is a serine/threonine-selective holoenzyme composed of a catalytic, scaffolding, and regulatory subunit. In the heart, PP2A activity is requisite for cardiac excitation-contraction coupling and central in adrenergic signaling. We found that mice deficient in the PP2A regulatory subunit B56a (1 of 13 regulatory subunits) had altered PP2A signaling in the heart that was associated with changes in cardiac physiology, suggesting that the B56a regulatory subunit had an autoinhibitory role that suppressed excess PP2A activity. The increase in PP2A activity in the mice with reduced B56a expression resulted in slower heart rates and increased heart rate variability, conduction defects, and increased sensitivity of heart rate to parasympathetic agonists. Increased PP2A activity in B56α+/- myocytes resulted in reduced Ca2+ waves and sparks, which was associated with decreased phosphorylation (and thus decreased activation) of the ryanodine receptor RyR2, an ion channel on intracellularmembranes that is involved in Ca2+ regulation in cardiomyocytes. In line with an autoinhibitory role for B56a, in vivo expression of B56a in the absence of altered abundance of other PP2A subunits decreased basal phosphatase activity. Consequently, in vivo expression of B56a suppressed parasympathetic regulation of heart rate and increased RyR2 phosphorylation in cardiomyocytes. These data show that an integral component of the PP2A holoenzyme has an important inhibitory role in controlling PP2A enzyme activity in the heart.
- Subjects
PHOSPHOPROTEIN phosphatases; THREONINE; PARASYMPATHETIC nervous system; HEART cells; RYANODINE receptors
- Publication
Science Signaling, 2015, Vol 8, Issue 386, p1
- ISSN
1945-0877
- Publication type
Article
- DOI
10.1126/scisignal.aaa5876