Heart failure is a major cause of death in the developed world and a growing health-care concern. In the February 28 Science, Joachim Schmitt and colleagues report the discovery of a mutation in patients suffering from inherited dilated cardiomyopathy with refractory congestive heart disease (Science, 299:1410-1413, February 28, 2003).

Schmitt et al. identified a dominant missense mutation (Arg<Cys) at residue 9 in phospholamban (PLN) — a 52-amino acid transmembrane phosphoprotein that regulates the Ca2+ ATPase pump (SERCA2a). They generated transgenic mice expressing the mutant PLNR9C in the heart and observed biventral cardiac dilation and progressive cardiomyopathy resembling human symptoms. Tissue culture experiments demonstrated that the PLNR9C mutant form trapped protein kinase A (PKA), which led to inhibition of the phosphorylation of wild-type PLNWT protein and delayed decay of Ca2+ transients.

Manipulating Ca2+ handling and/or PLN activity may provide a therapeutic opportunity for treating human...

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