{"doi":"10.1152/ajpheart.00225.2006","title":"Acute modulation of PP2a and troponin I phosphorylation in ventricular myocytes: studies with a novel PP2a peptide inhibitor","abstract":"<jats:p>The present study demonstrates that acute activation with either β-adrenergic receptor agonists or H<jats:sub>2</jats:sub>O<jats:sub>2</jats:sub>treatment increases protein phosphatase 2a (PP2a) activity in ventricular myocytes. PP2a activation occurs concomitant with an increase in methylation of PP2a, changes in localization of a PP2a targeting subunit PP2aB56α, and a decrease in phosphorylation of PP2a substrates, such as troponin I (TnI) and ERK in ventricular myocytes. Okadaic acid, a well-established pharmacological inhibitor of PP2a, and the peptide Thr-Pro-Asp-Tyr-Phe-Leu (TPDYFL) were used to block PP2a methylation, localization, and phosphorylations. TPDYFL is a highly conserved sequence of the PP2a catalytic subunit COOH-terminus. Specifically, both okadaic acid and the peptide increased β-adrenergic-cAMP-dependent phosphorylation of TnI and blocked the β-adrenergic-cAMP-dependent translocation of PP2aB56α. TPDYFL, but not a scrambled version of this sequence, blocked H<jats:sub>2</jats:sub>O<jats:sub>2</jats:sub>-induced changes in PP2a methylation and TnI dephosphorylation. Okadaic acid produces similar inhibition of H<jats:sub>2</jats:sub>O<jats:sub>2</jats:sub>effects. Thus we propose that the novel peptide TPDYFL acts as an inhibitor of PP2a activity and may be a useful tool to increase our understanding of how PP2a is regulated and the role of PP2a in a variety of physiological and pathological processes. In addition, the present study is consistent with acute β-adrenergic receptor activation and H<jats:sub>2</jats:sub>O<jats:sub>2</jats:sub>exposure, simultaneously activating kinases and PP2a to work on common substrates, such as TnI. We hypothesize that dual activation of opposing enzymes provides for a tighter regulation of substrate phosphorylations in ventricular myocytes.</jats:p>","journal":"American Journal of Physiology-Heart and Circulatory Physiology","year":2007,"id":632144,"datarank":0.5289540786924243,"base_score":3.5263605246161616,"endowment":3.5263605246161616,"self_citation_contribution":0.5289540786924243,"citation_network_contribution":0.0,"self_endowment_contribution":0.5289540786924243,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":33,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1638515,"name":"Bradford C. 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Okadaic acid, a well-established pharmacological inhibitor of PP2a, and the peptide Thr-Pro-Asp-Tyr-Phe-Leu (TPDYFL) were used to block PP2a methylation, localization, and phosphorylations. TPDYFL is a highly conserved sequence of the PP2a catalytic subunit COOH-terminus. Specifically, both okadaic acid and the peptide increased β-adrenergic-cAMP-dependent phosphorylation of TnI and blocked the β-adrenergic-cAMP-dependent translocation of PP2aB56α. TPDYFL, but not a scrambled version of this sequence, blocked H<jats:sub>2</jats:sub>O<jats:sub>2</jats:sub>-induced changes in PP2a methylation and TnI dephosphorylation. Okadaic acid produces similar inhibition of H<jats:sub>2</jats:sub>O<jats:sub>2</jats:sub>effects. Thus we propose that the novel peptide TPDYFL acts as an inhibitor of PP2a activity and may be a useful tool to increase our understanding of how PP2a is regulated and the role of PP2a in a variety of physiological and pathological processes. In addition, the present study is consistent with acute β-adrenergic receptor activation and H<jats:sub>2</jats:sub>O<jats:sub>2</jats:sub>exposure, simultaneously activating kinases and PP2a to work on common substrates, such as TnI. 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