title: Akt regulates L-type Ca2+ channel activity by modulating Cavalpha1 protein stability.
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(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.
authors.affiliation: Division of Cardiology, Department of Medicine, University of California-San Diego, La Jolla, CA 92093, USA. daniele.catalucci@itb.cnr.it
authors.forename: Daniele
authors.initials: D
authors.lastname: Catalucci
authors.forename: Deng-Hong
authors.initials: DH
authors.lastname: Zhang
authors.forename: Jaime
authors.initials: J
authors.lastname: DeSantiago
authors.forename: Franck
authors.initials: F
authors.lastname: Aimond
authors.forename: Guillaume
authors.initials: G
authors.lastname: Barbara
authors.forename: Jean
authors.initials: J
authors.lastname: Chemin
authors.forename: Désiré
authors.initials: D
authors.lastname: Bonci
authors.forename: Eckard
authors.initials: E
authors.lastname: Picht
authors.forename: Francesca
authors.initials: F
authors.lastname: Rusconi
authors.forename: Nancy D
authors.initials: ND
authors.lastname: Dalton
authors.forename: Kirk L
authors.initials: KL
authors.lastname: Peterson
authors.forename: Sylvain
authors.initials: S
authors.lastname: Richard
authors.forename: Donald M
authors.initials: DM
authors.lastname: Bers
authors.forename: Joan Heller
authors.initials: JH
authors.lastname: Brown
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Condorelli
mesh_terms: D064413:3-Phosphoinositide-Dependent Protein Kinases; D020816:Amino Acid Motifs; D000818:Animals; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000378:metabolism*; D020013:Calcium Signaling; D002311:Cardiomyopathy, Dilated / Q000201:enzymology* / Q000209:etiology; D002462:Cell Membrane / Q000201:enzymology; D002478:Cells, Cultured; D017124:Conserved Sequence; D004195:Disease Models, Animal; D008297:Male; D008564:Membrane Potentials; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000201:enzymology*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics; D055550:Protein Stability; D021122:Protein Subunits; D021381:Protein Transport; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013629:Tamoxifen; D013997:Time Factors; D014162:Transfection
chemical_list: D020746:Calcium Channels, L-Type; D021122:Protein Subunits; D011993:Recombinant Fusion Proteins; D013629:Tamoxifen; D064413:3-Phosphoinositide-Dependent Protein Kinases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt