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 Cava1 contains highly conserved PEST sequences (signals for rapid protein degradation), and in-frame deletion of these PEST sequences results in increased Cava1 protein levels. Our findings show that Akt-dependent phosphorylation of Cavb2, the LTCC chaperone for Cava1, antagonizes Cavva1 protein degradation by preventing Cava1 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.
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 Cav ! 1 contains highly conserved PEST sequences (signals for rapid protein degradation), and in-frame deletion of these PEST sequences results in increased Cav ! 1 protein levels. Our fi ndings show that Akt-dependent phosphorylation of Cav " 2, the LTCC chaperone for Cav ! 1, antagonizes Ca v ! 1 protein degradation by preventing Cav ! 1 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 infl uence cardiac myocyte Ca 2+ entry, Ca 2+ handling, and contractility
Akt regulates L-type Ca2+ channel activity by modulating Cava1 protein stability
Daniele Catalucci;
2009
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 Cav ! 1 contains highly conserved PEST sequences (signals for rapid protein degradation), and in-frame deletion of these PEST sequences results in increased Cav ! 1 protein levels. Our fi ndings show that Akt-dependent phosphorylation of Cav " 2, the LTCC chaperone for Cav ! 1, antagonizes Ca v ! 1 protein degradation by preventing Cav ! 1 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 infl uence cardiac myocyte Ca 2+ entry, Ca 2+ handling, and contractilityI documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
