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.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
3-Phosphoinositide-Dependent Protein Kinases
-
Amino Acid Motifs
-
Animals
-
Calcium Channels, L-Type / genetics
-
Calcium Channels, L-Type / metabolism*
-
Calcium Signaling*
-
Cardiomyopathy, Dilated / enzymology*
-
Cardiomyopathy, Dilated / etiology
-
Cell Membrane / enzymology
-
Cells, Cultured
-
Conserved Sequence
-
Disease Models, Animal
-
Male
-
Membrane Potentials
-
Mice
-
Mice, Inbred C57BL
-
Mice, Knockout
-
Mice, Transgenic
-
Mutation
-
Myocardial Contraction
-
Myocytes, Cardiac / enzymology*
-
Phosphorylation
-
Protein Serine-Threonine Kinases / deficiency
-
Protein Serine-Threonine Kinases / genetics
-
Protein Stability
-
Protein Subunits
-
Protein Transport
-
Proto-Oncogene Proteins c-akt / genetics
-
Proto-Oncogene Proteins c-akt / metabolism*
-
Recombinant Fusion Proteins / metabolism
-
Tamoxifen
-
Time Factors
-
Transfection
Substances
-
Calcium Channels, L-Type
-
Protein Subunits
-
Recombinant Fusion Proteins
-
Tamoxifen
-
3-Phosphoinositide-Dependent Protein Kinases
-
Protein Serine-Threonine Kinases
-
Proto-Oncogene Proteins c-akt