Publication Date:
2003-03-01
Description:
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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Schmitt, Joachim P -- Kamisago, Mitsuhiro -- Asahi, Michio -- Li, Guo Hua -- Ahmad, Ferhaan -- Mende, Ulrike -- Kranias, Evangelia G -- MacLennan, David H -- Seidman, J G -- Seidman, Christine E -- New York, N.Y. -- Science. 2003 Feb 28;299(5611):1410-3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Genetics, Harvard Medical School and Howard Hughes Medical Institute, 200 Longwood Avenue, Boston, MA 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/12610310" target="_blank"〉PubMed〈/a〉
Keywords:
Amino Acid Sequence
;
Amino Acid Substitution
;
Animals
;
Calcium/metabolism
;
Calcium Signaling
;
Calcium-Binding Proteins/chemistry/*genetics/*physiology
;
Calcium-Transporting ATPases/antagonists & inhibitors/metabolism
;
Cardiomegaly
;
Cardiomyopathy, Dilated/*genetics/pathology/physiopathology
;
Cell Line
;
Cyclic AMP-Dependent Protein Kinases/metabolism
;
Female
;
Heart Failure/*genetics/pathology/physiopathology
;
Heart Ventricles/metabolism/pathology
;
Humans
;
Lod Score
;
Male
;
Mice
;
Mice, Transgenic
;
Molecular Sequence Data
;
Muscle Cells/metabolism/physiology
;
*Mutation, Missense
;
Myocardial Contraction
;
Myocardium/pathology
;
Pedigree
;
Phosphorylation
;
Sarcoplasmic Reticulum Calcium-Transporting ATPases
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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