Akt increases sarcoplasmic reticulum Ca2+ cycling by direct phosphorylation of phospholamban at Thr17

Daniele Catalucci, Michael V G Latronico, Marcello Ceci, Francesca Rusconi, Howard S. Young, Paolo Gallo, Marco Santonastasi, Alfonso Bellacosa, Joan Heller Brown, Gianluigi Condorelli

Research output: Contribution to journalArticlepeer-review

Abstract

Cardiomyocytes adapt to physical stress by increasing their size while maintaining cell function. The serine/threonine kinase Akt plays a critical role in this process of adaptation. We previously reported that transgenic overexpression of an active form of Akt (Akt-E40K) in mice results in increased cardiac contractility and cell size, as well as improved sarcoplasmic reticulum (SR) Ca2+ handling. Because it is not fully elucidated, we decided to study the molecular mechanism by which Akt-E40K overexpression improves SR Ca2+ handling. To this end, SR Ca2+ uptake and the phosphorylation status of phospholamban (PLN) were evaluated in heart extracts from wild-type and Akt-E40 K mice and mice harboring inducible and cardiac specific knock-out of phosphatidylinositol-dependent kinase-1, the upstream activator of Akt. Moreover, the effect of Akt was assessed in vitro by overexpressing a mutant Akt targeted preferentially to the SR, and by biochemical assays to evaluate potential interaction with PLN. We found that when activated, Akt interacts with and phosphorylates PLN at Thr17, the Ca2+-calmodulin-dependent kinase IIδ site, whereas silencing Akt signaling, through the knock-out of phosphatidylinositol-dependent kinase-1, resulted in reduced phosphorylation of PLN at Thr17. Furthermore, overexpression of SR-targeted Akt in cardiomyocytes improved Ca2+ handling without affecting cell size. Thus, we describe here a new mechanism whereby the preferential translocation of Akt to the SR is responsible for enhancement of contractility without stimulation of hypertrophy.

Original languageEnglish
Pages (from-to)28180-28187
Number of pages8
JournalJournal of Biological Chemistry
Volume284
Issue number41
DOIs
Publication statusPublished - Oct 9 2009

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

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