Akt regulates L-type Ca2 channel activity by modulating Ca-v alpha 1 protein stability

作者：Catalucci Daniele^*; Zhang Deng Hong; DeSantiago Jaime; Aimond Franck; Barbara Guillaume; Chemin Jean; Bonci Desire; Picht Eckard; Rusconi Francesca; Dalton Nancy D; Peterson Kirk L; Richard Sylvain; Bers Donald M; Brown Joan Heller; Condorelli Gianluigi

来源：The Journal of Cell Biology, 2009, 184(6): 923-933.

DOI：10.1083/jcb.200805063

The insulin IGF-1-PI3K-Akt signaling pathway has been suggested to improve cardiac inotropism and increase Ca2 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 Ca2 channel (LTCC) protein density. The pore-forming channel subunit Ca-v alpha 1 contains highly conserved PEST sequences (signals for rapid protein degradation), and in-frame deletion of these PEST sequences results in increased Ca-v alpha 1 protein levels. Our findings show that Akt-dependent phosphorylation of Ca-v alpha 2, the LTCC chaperone for Ca-v alpha 1, antagonizes Ca-v alpha 1 protein degradation by preventing Ca-v alpha 1 PEST sequence recognition, leading to increased LTCC density and the consequent modulation of Ca2 channel function. This novel mechanism by which Akt modulates LTCC stability could profoundly influence cardiac myocyte Ca2 entry, Ca2 handling, and contractility.

• 出版日期2009-3-23