title: Protein phosphatase 2A regulatory subunit B56α limits phosphatase activity in the heart.
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.
authors.affiliation: 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.
authors.forename: Sean C
authors.initials: SC
authors.lastname: Little
authors.affiliation: 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.
authors.forename: Jerry
authors.initials: J
authors.lastname: Curran
authors.affiliation: 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.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Makara
authors.affiliation: 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.
authors.forename: Crystal F
authors.initials: CF
authors.lastname: Kline
authors.affiliation: 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.
authors.forename: Hsiang-Ting
authors.initials: HT
authors.lastname: Ho
authors.affiliation: 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.
authors.forename: Zhaobin
authors.initials: Z
authors.lastname: Xu
authors.affiliation: 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.
authors.forename: Xiangqiong
authors.initials: X
authors.lastname: Wu
authors.affiliation: 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.
authors.forename: Iuliia
authors.initials: I
authors.lastname: Polina
authors.affiliation: 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.
authors.forename: Hassan
authors.initials: H
authors.lastname: Musa
authors.affiliation: 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.
authors.forename: Allison M
authors.initials: AM
authors.lastname: Meadows
authors.affiliation: 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.
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Carnes
authors.affiliation: 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.
authors.forename: Brandon J
authors.initials: BJ
authors.lastname: Biesiadecki
authors.affiliation: 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.
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Davis
authors.affiliation: 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.
authors.forename: Noah
authors.initials: N
authors.lastname: Weisleder
authors.affiliation: 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.
authors.forename: Sandor
authors.initials: S
authors.lastname: Györke
authors.affiliation: Cardiovascular Research Institute, Departments of Molecular Physiology and Biophysics, and Medicine (Cardiology), Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Xander H
authors.initials: XH
authors.lastname: Wehrens
authors.affiliation: 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.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Hund
authors.affiliation: 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.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Mohler
mesh_terms: D000818:Animals; D020013:Calcium Signaling; D051379:Mice; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D009206:Myocardium / Q000201:enzymology*; D032383:Myocytes, Cardiac / Q000201:enzymology*; D054648:Protein Phosphatase 2 / Q000235:genetics / Q000378:metabolism*; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism
chemical_list: D009124:Muscle Proteins; D019837:Ryanodine Receptor Calcium Release Channel; C000592748:ryanodine receptor 2. mouse; C551901:Ppp2r5a protein, mouse; D054648:Protein Phosphatase 2