%0 Journal Article %1 Schmitt2003 %A Schmitt, J. P. %A Kamisago, M. %A Asahi, M. %A Li, G. H. %A Ahmad, F. %A Mende, U. %A Kranias, E. G. %A MacLennan, D. H. %A Seidman, J. G. %A Seidman, C. E. %D 2003 %J Science %K & *Mutation, AMP-Dependent ATPases ATPases/antagonists Acid Amino Animals Calcium Calcium-Binding Calcium-Transporting Calcium/metabolism Cardiomegaly Cardiomyopathy, Cell Cells/metabolism/physiology Contraction Cyclic Data Dilated/*genetics/pathology/physiopathology Failure/*genetics/pathology/physiopathology Female Heart Humans Kinases/metabolism Line Lod Male Mice Missense Molecular Muscle Myocardial Myocardium/pathology Pedigree Phosphorylation Protein Proteins/chemistry/*genetics/*physiology Reticulum Sarcoplasmic Score Sequence Signaling Substitution Transgenic Ventricles/metabolism/pathology inhibitors/metabolism %N 5611 %P 1410-3 %T Dilated cardiomyopathy and heart failure caused by a mutation in phospholamban %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12610310 %V 299 %X 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.

@article{Schmitt2003, abstract = {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.}, added-at = {2010-12-14T18:12:02.000+0100}, author = {Schmitt, J. P. and Kamisago, M. and Asahi, M. and Li, G. H. and Ahmad, F. and Mende, U. and Kranias, E. G. and MacLennan, D. H. and Seidman, J. G. and Seidman, C. E.}, biburl = {https://www.bibsonomy.org/bibtex/2ca3a46c7f89bb13797877f6f6e5a893c/pharmawuerz}, endnotereftype = {Journal Article}, interhash = {d2fee6ac55ee2c32d81086be1a53d6eb}, intrahash = {ca3a46c7f89bb13797877f6f6e5a893c}, issn = {1095-9203 (Electronic) 1095-9203 (Linking)}, journal = {Science}, keywords = {& *Mutation, AMP-Dependent ATPases ATPases/antagonists Acid Amino Animals Calcium Calcium-Binding Calcium-Transporting Calcium/metabolism Cardiomegaly Cardiomyopathy, Cell Cells/metabolism/physiology Contraction Cyclic Data Dilated/*genetics/pathology/physiopathology Failure/*genetics/pathology/physiopathology Female Heart Humans Kinases/metabolism Line Lod Male Mice Missense Molecular Muscle Myocardial Myocardium/pathology Pedigree Phosphorylation Protein Proteins/chemistry/*genetics/*physiology Reticulum Sarcoplasmic Score Sequence Signaling Substitution Transgenic Ventricles/metabolism/pathology inhibitors/metabolism}, month = {Feb 28}, note = {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 Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S. United States Science (New York, N.Y.) Science. 2003 Feb 28;299(5611):1410-3.}, number = 5611, pages = {1410-3}, shorttitle = {Dilated cardiomyopathy and heart failure caused by a mutation in phospholamban}, timestamp = {2010-12-14T18:21:26.000+0100}, title = {Dilated cardiomyopathy and heart failure caused by a mutation in phospholamban}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12610310}, volume = 299, year = 2003 }