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(v)alpha1 contains highly conserved PEST sequences (signals for rapid protein degradation), and in-frame deletion of these PEST sequences results in increased Ca(v)alpha1 protein levels. Our findings show that Akt-dependent phosphorylation of Ca(v)beta2, the LTCC chaperone for Ca(v)alpha1, antagonizes Ca(v)alpha1 protein degradation by preventing Ca(v)alpha1 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 myocyte Ca(2+) entry, Ca(2+) handling, and contractility.
Akt regulates L-type Ca2+ channel activity by modulating Cavalpha1 protein stability / D. Catalucci, D.H. Zhang, J. DeSantiago, F. Aimond, G. Barbara, J. Chemin, D. Bonci, E. Picht, F. Rusconi, N.D. Dalton, K.L. Peterson, S. Richard, D.M. Bers, J.H. Brown, G. Condorelli. - In: THE JOURNAL OF CELL BIOLOGY. - ISSN 0021-9525. - 184:6(2009 Mar 23), pp. 923-933.
|Titolo:||Akt regulates L-type Ca2+ channel activity by modulating Cavalpha1 protein stability|
RUSCONI, FRANCESCA (Secondo)
CONDORELLI, GIANLUIGI (Ultimo)
|Parole Chiave:||Calcium signaling ; calcium channels L-type ; cardiomyopathy dilated ; cell membrane ; disease models animal ; male ; membrane potentials ; mice myocardial contraction ; myocytes cardiac ; phosphorylation ; protein stability ; protein subunits ; protein transport ; protein-serine-threonine kinases ; proto-pncogene proteins c-akt|
|Settore Scientifico Disciplinare:||Settore MED/11 - Malattie dell'Apparato Cardiovascolare|
|Data di pubblicazione:||23-mar-2009|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1083/jcb.200805063|
|Appare nelle tipologie:||01 - Articolo su periodico|