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Protein phosphatase 2A regulatory subunit B56? 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 B56? (1 of 13 regulatory subunits) had altered PP2A signaling in the heart that was associated with changes in cardiac physiology, suggesting that the B56? regulatory subunit had an autoinhibitory role that suppressed excess PP2A activity. The increase in PP2A activity in the mice with reduced B56? 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 B56?(+/-) 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 B56?, in vivo expression of B56? in the absence of altered abundance of other PP2A subunits decreased basal phosphatase activity. Consequently, in vivo expression of B56? 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.

SUBMITTER: Little SC

PROVIDER: S-EPMC4680974 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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

Little Sean C SC Curran Jerry J Makara Michael A MA Kline Crystal F CF Ho Hsiang-Ting HT Xu Zhaobin Z Wu Xiangqiong X Polina Iuliia I Musa Hassan H Meadows Allison M AM Carnes Cynthia A CA Biesiadecki Brandon J BJ Davis Jonathan P JP Weisleder Noah N Györke Sandor S Wehrens Xander H XH Hund Thomas J TJ Mohler Peter J PJ

Science signaling 20150721 386

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 a ...[more]

PMID: 26198358

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Project description:BackgroundWnt signaling is a key regulator of development and tumorigenesis. Protein phosphatase 2A (PP2A), which consists of a catalytic C, a structural A, and a regulatory B subunit, plays diverse roles in Wnt signaling through its B56 subunits. B56 is a multigene family encoding for proteins with a conserved core domain and divergent amino- and carboxy-termini. Ectopic B56alpha and B56gamma reduce beta-catenin abundance and B56alpha reduces Wnt-dependent transcription, suggesting that B56alpha and B56gamma inhibit Wnt signaling. In contrast, B56epsilon is required for Wnt signaling. Knowledge of where and when B56 subunits are expressed during Xenopus development will aid in our understanding of their roles in Wnt signaling.ResultsWe have undertaken expression analyses of B56alpha and B56gamma in Xenopus laevis. We cloned Xenopus B56alpha; it is 88% identical to human B56alpha. Xenopus B56gamma is 94% identical with human B56gamma, however, a novel evolutionarily conserved mixed-isoform transcript was identified that contains a B56delta-like amino-terminal domain and a B56gamma core domain. The B56delta-like variable domain exon is located upstream of the B56gamma variable domain exon at the human B56gamma locus, suggesting that the mixed-isoform transcript is due to alternative splicing. B56gamma transcripts with different 3' ends were identified that lack or possess a 35 base pair sequence, resulting in either a transcript similar to human B56gamma1, or an uncharacterized evolutionarily conserved sequence. Real time RT-PCR analyses revealed that B56alpha is expressed at moderate levels before the midblastula transition (MBT), at reduced levels during gastrulation and neurulation, and at high levels during organogenesis, while B56gamma is expressed at low levels until organogenesis. B56alpha is enriched in the ventral hemisphere pre-MBT, while B56gamma is ventrally enriched post-MBT. Aalpha, Abeta, Calpha and Cbeta are expressed in early Xenopus development, suggesting the presence of a functional heterotrimer.ConclusionOur data suggest that B56 functional diversity is achieved in part through the synthesis of a novel mixed-isoform B56delta/gamma transcript. Our data also suggest that B56alpha functions pre-MBT, inhibiting Wnt signaling on the ventral side of the embryo, and again during organogenesis, while B56gamma functions primarily post-MBT.

Dataset Information

Protein phosphatase 2A regulatory subunit B56? limits phosphatase activity in the heart.

Publications

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

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