Protein phosphatase 2A regulatory subunit B56α limits phosphatase activity in the heart
Open accessAbstract
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.
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Isolated B56α-/- cardiomyocytes showed reduced Ca2+ waves and spark frequency under β-adrenergic stimulation.
“In isolated B56α -/-cardiomyocytes, reduced Ca 2+ waves and spark frequency in the presence of sympathetic stimulation (β-adrenergic stimulus) were observed.”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [68]
B56α knockout had diminished RyR2 Ser2808 and Ser2814 phosphorylation, correlating with reduced Ca2+ sensitivity of RyR2.
“Further in-depth analysis revealed a diminished phosphorylation of the ryanodine receptor (RyR 2 ) at Ser2808 and Ser2814, correlating with reduced Ca 2+ sensitivity of RyR 2 [68].”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [68]
Increased cardiac B56α expression via adenoviral vector caused higher resting heart rate, increased peak heart rate in response to exercise or β-adrenergic stimulation, and a blunted parasympathetic response.
“in a model with increased cardiac B56α expression through injection of an adenoviral B56α expression vector in the myocardium, a higher resting heart rate was found, alongside an increased peak heart rate in response to exercise or β-adrenergic stimulation and a blunted response to parasympathetic stimulation.”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [68]
B56α knockout mice had reduced intrinsic heart rate, conduction defects, increased sensitivity to parasympathetic stimulation, and resistance to catecholamine- and exercise-induced arrhythmias.
“These mice suffered from a reduced intrinsic heart rate, conduction defects, and increased sensitivity to parasympathetic stimulation, as evident from their relative resistance to catecholamine and exercise-induced arrhythmias.”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [68]
This was associated with increased RyR2 Ser2808 and Ser2814 phosphorylation.
“This was associated with an increase in RyR 2 phosphorylation (Ser2808, Ser2814) [68].”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [68]
Complete constitutive B56α knockout increased cardiac PP2A activity in both heterozygous and homozygous mice, leading to a distinct phenotype.
“the complete, constitutive KO of B56α (Ppp2r5a), remarkably, increased cardiac PP2A activity (measured on pNPP as a substrate and using the selective pharmacological PP2A inhibitor fostriecin as a specificity control), both in heterozygous and homozygous mice, leading to a completely distinct phenotype [68].”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [68]
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Physiologic functions of PP2A: Lessons from genetically modified mice
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- Authors
- Little, S. C., Curran, J., Makara, M. A., Kline, C. F., Ho, H.-T., Xu, Z., Wu, X., Polina, I., Musa, H., Meadows, A. M., Carnes, C. A., Biesiadecki, B. J., Davis, J. P., Weisleder, N., Györke, S., Wehrens, X. H., Hund, T. J., & Mohler, P. J.
- Affiliations
- The Ohio State University Wexner Medical Center (US)
- Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA.
- Baylor College of Medicine (US)
- Corresponding author
- Mohler, Peter J.
- ORCID
- Venue
- Science Signaling
- Published
- 2015-07-21
- Volume
- 8
- Issue
- 386
- Pages
- ra72-ra72
- ISSN
- 1937-9145 (ISSN-L)
- 1945-0877
- PMC
- PMC4680974
- OpenAlex
- W2223519024
- Cited by
- 53
- References
- 36
- Citations by year
- 2025: 6 · 2024: 3 · 2023: 2 · 2022: 6 · 2021: 5 · 2020: 2 · 2019: 6 · 2018: 6 · 2017: 9 · 2016: 6 · 2015: 2
- FWCI
- 5.58
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science Signaling (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH (HL084583, HL083422, HL114383, HL114893, HL098039, HL089598, HL091947, HL117641, HL114940)
- American Heart Association
- Fondation Leducq
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- protein phosphatase 2A, cardiac excitation-contraction coupling, calcium sparks, heart rate variability, cardiac conduction disorders, cardiomyocytes
- MeSH terms
- Animals, Muscle Proteins, Myocardium, Mice, Knockout, Ryanodine Receptor Calcium Release Channel, Calcium Signaling, Myocytes, Cardiac, Mice, Protein Phosphatase 2
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