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

Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee

Submitted 2 March 2006 ; accepted in final form 23 September 2006

The present study demonstrates that acute activation with either -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, 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 -adrenergic-cAMP-dependent phosphorylation of TnI and blocked the -adrenergic-cAMP-dependent translocation of PP2aB56. TPDYFL, but not a scrambled version of this sequence, blocked H₂O₂-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 -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.

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

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