| First Author | Domes K | Year | 2011 |
| Journal | J Biol Chem | Volume | 286 |
| Issue | 39 | Pages | 33863-71 |
| PubMed ID | 21832054 | Mgi Jnum | J:176723 |
| Mgi Id | MGI:5292578 | Doi | 10.1074/jbc.M111.252312 |
| Citation | Domes K, et al. (2011) Truncation of murine cav1.2 at asp-1904 results in heart failure after birth. J Biol Chem 286(39):33863-71 |
| abstractText | The carboxyl-terminal intracellular tail of the l-type Ca(2+) channel Ca(V)1.2 modulates various aspects of channel activity. For example, deletion of the carboxyl-terminal sequence at Ser-1905 increased Ca(V)1.2 currents in an expression model. To verify this finding in an animal model, we inserted three stop codons at the corresponding Asp-1904 in the murine Ca(V)1.2 gene. Mice homozygous for the Stop mutation (Stop/Stop mice) were born at a Mendelian ratio but died after birth. Stop/Stop hearts showed reduced beating frequencies and contractions. Surprisingly, Stop/Stop cardiomyocytes displayed reduced I(Ba) and a minor expression of the Ca(V)1.2(Stop) protein. In contrast, expression of the Ca(V)1.2(Stop) protein was normal in pooled smooth muscle samples from Stop/Stop embryos. As the Ca(V)1.2 channel exists in a cardiac and smooth muscle splice variant, HK1 and LK1, respectively, we analyzed the consequences of the deletion of the carboxyl terminus in the respective splice variant using the rabbit Ca(V)1.2 clone expressed in HEK293 cells. HEK293 cells transfected with the HK1(Stop) channel showed a reduced I(Ba) and Ca(V)1.2 expression. Treatment with proteasome inhibitors increased the expression of HK1(Stop) protein and I(Ba) in HEK293 cells and in Stop/Stop cardiomyocytes indicating that truncation of Ca(V)1.2 containing the cardiac exon 1a amino terminus results in proteasomal degradation of the translated protein. In contrast, HEK293 cells transfected with the LK1(Stop) channel had normal I(Ba) and Ca(V)1.2 expression. These findings indicate that absence of the carboxyl-terminal tail differentially determines the fate of the cardiac and smooth muscle splice variant of the Ca(V)1.2 channel in the mouse. |
