Akt regulates L-type Ca 2+ channel activity by modulating Ca vα1 protein stability

Daniele Catalucci, Deng Hong Zhang, Jaime Desantiago, Franck Aimond, Guillaume Barbara, Jean Chemin, Désiré Bonci, Eckard Picht, Francesca Rusconi, Nancy D. Dalton, Kirk L. Peterson, Sylvain Richard, Donald M Bers, Joan Heller Brown, Gianluigi Condorelli

Research output: Contribution to journalArticle

80 Scopus citations

Abstract

The insulin IGF-1 -PI3K-Akt signaling pathway has been suggested to improve cardiac inotropism and increase Ca 2+ handling through the effects of the protein kinase Akt. However, the underlying molecular mechanisms remain largely unknown. In this study, we provide evidence for an unanticipated regulatory function of Akt controlling L-type Ca 2+ channel (LTCC) protein density. The pore-forming channel subunit Ca vα1 contains highly conserved PEST sequences (signals for rapid protein degradation), and in-frame deletion of these PEST sequences results in increased Ca vα1 protein levels. Our findings show that Akt-dependent phosphorylation of Ca vβ2, the LTCC chaperone for Ca vα1, antagonizes Ca vα1 protein degradation by preventing Ca vα1 PEST sequence recognition, leading to increased LTCC density and the consequent modulation of Ca 2+ channel function. This novel mechanism by which Akt modulates LTCC stability could profoundly influence cardiac myo- cyte Ca 2+ entry, Ca 2+ handling, and contractility.

Original languageEnglish (US)
Pages (from-to)923-933
Number of pages11
JournalJournal of Cell Biology
Volume184
Issue number6
DOIs
StatePublished - Mar 23 2009

ASJC Scopus subject areas

  • Cell Biology
  • Medicine(all)

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    Catalucci, D., Zhang, D. H., Desantiago, J., Aimond, F., Barbara, G., Chemin, J., Bonci, D., Picht, E., Rusconi, F., Dalton, N. D., Peterson, K. L., Richard, S., Bers, D. M., Brown, J. H., & Condorelli, G. (2009). Akt regulates L-type Ca 2+ channel activity by modulating Ca vα1 protein stability. Journal of Cell Biology, 184(6), 923-933. https://doi.org/10.1083/jcb.200805063