AI Article Synopsis
- The insulin IGF-1-PI3K-Akt signaling pathway may enhance heart function by affecting calcium handling through Akt, but the specific mechanisms were unclear.
- Akt has been found to regulate the density of L-type Ca(2+) channels (LTCC) by affecting the protein levels of Ca(v)alpha1, which is crucial for calcium flow in heart muscle cells.
- The phosphorylation of Ca(v)beta2 by Akt prevents the degradation of Ca(v)alpha1, leading to higher LTCC density and potentially improving calcium entry and heart contraction.
Article 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.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2699149 | PMC |
| http://dx.doi.org/10.1083/jcb.200805063 | DOI Listing |
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