Format

Send to

Choose Destination
Sci Signal. 2015 Jul 21;8(386):ra72. doi: 10.1126/scisignal.aaa5876.

Protein phosphatase 2A regulatory subunit B56α limits phosphatase activity in the heart.

Author information

1
Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA. Department of Physiology and Cell Biology, The Ohio State University Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA.
2
Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA. Department of Biomedical Engineering, College of Engineering, The Ohio State University, Columbus, OH 43210, USA.
3
Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA. College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA.
4
Cardiovascular Research Institute, Departments of Molecular Physiology and Biophysics, and Medicine (Cardiology), Baylor College of Medicine, Houston, TX 77030, USA.
5
Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA. Department of Physiology and Cell Biology, The Ohio State University Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA. Department of Internal Medicine, The Ohio State University Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA. peter.mohler@osumc.edu.

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 B56α (1 of 13 regulatory subunits) had altered PP2A signaling in the heart that was associated with changes in cardiac physiology, suggesting that the B56α regulatory subunit had an autoinhibitory role that suppressed excess PP2A activity. The increase in PP2A activity in the mice with reduced B56α 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 Ca(2+) waves and sparks, which was associated with decreased phosphorylation (and thus decreased activation) of the ryanodine receptor RyR2, an ion channel on intracellular membranes that is involved in Ca(2+) regulation in cardiomyocytes. In line with an autoinhibitory role for B56α, in vivo expression of B56α in the absence of altered abundance of other PP2A subunits decreased basal phosphatase activity. Consequently, in vivo expression of B56α 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.

PMID:
26198358
PMCID:
PMC4680974
DOI:
10.1126/scisignal.aaa5876
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center