4.6 Article

Acute modulation of PP2a and troponin I phosphorylation in ventricular myocytes: studies with a novel PP2a peptide inhibitor

出版社

AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpheart.00225.2006

关键词

beta-adrenergic receptor; hydrogen peroxide; peptide inhibition; protein phosphatase 2a

资金

  1. NHLBI NIH HHS [HL-48839] Funding Source: Medline

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The present study demonstrates that acute activation with either beta-adrenergic receptor agonists or H2O2 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 PP2aB56 alpha, 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 beta-adrenergic-cAMP-dependent phosphorylation of TnI and blocked the beta-adrenergic-cAMP-dependent translocation of PP2aB56 alpha. TPDYFL, but not a scrambled version of this sequence, blocked H(2)O(2)induced changes in PP2a methylation and TnI dephosphorylation. Okadaic acid produces similar inhibition of H2O2 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 beta-adrenergic receptor activation and H2O2 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.

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