| First Author | Schmitt JP | Year | 2003 |
| Journal | Science | Volume | 299 |
| Issue | 5611 | Pages | 1410-3 |
| PubMed ID | 12610310 | Mgi Jnum | J:82353 |
| Mgi Id | MGI:2652326 | Doi | 10.1126/science.1081578 |
| Citation | Schmitt JP, et al. (2003) Dilated cardiomyopathy and heart failure caused by a mutation in phospholamban. Science 299(5611):1410-3 |
| abstractText | Molecular etiologies of heart failure, an emerging cardiovascular epidemic affecting 4.7 million Americans and costing 17.8 billion health-care dollars annually, remain poorly understood. Here we report that an inherited human dilated cardiomyopathy with refractory congestive heart failure is caused by a dominant Arg --> Cys missense mutation at residue 9 (R9C) in phospholamban (PLN), a transmembrane phosphoprotein that inhibits the cardiac sarcoplasmic reticular Ca2+-adenosine triphosphatase (SERCA2a) pump. Transgenic PLN(R9C) mice recapitulated human heart failure with premature death. Cellular and biochemical studies revealed that, unlike wild-type PLN, PLN(R9C) did not directly inhibit SERCA2a. Rather, PLN(R9C) trapped protein kinase A (PKA), which blocked PKA-mediated phosphorylation of wild-type PLN and in turn delayed decay of calcium transients in myocytes. These results indicate that myocellular calcium dysregulation can initiate human heart failure-a finding that may lead to therapeutic opportunities. |
