Akt regulates L-type Ca ²⁺ channel activity by modulating Ca _vα1 protein stability

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 _vα1 contains highly conserved PEST sequences (signals for rapid protein degradation), and in-frame deletion of these PEST sequences results in increased Ca _vα1 protein levels. Our findings show that Akt-dependent phosphorylation of Ca _vβ2, the LTCC chaperone for Ca _vα1, antagonizes Ca _vα1 protein degradation by preventing Ca _vα1 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 myo- cyte Ca ²⁺ entry, Ca ²⁺ handling, and contractility.