| pubmed-article:18212018 | rdf:type | pubmed:Citation | lld:pubmed |
| pubmed-article:18212018 | lifeskim:mentions | umls-concept:C0225828 | lld:lifeskim |
| pubmed-article:18212018 | lifeskim:mentions | umls-concept:C1521991 | lld:lifeskim |
| pubmed-article:18212018 | lifeskim:mentions | umls-concept:C0596988 | lld:lifeskim |
| pubmed-article:18212018 | lifeskim:mentions | umls-concept:C1516144 | lld:lifeskim |
| pubmed-article:18212018 | lifeskim:mentions | umls-concept:C1420822 | lld:lifeskim |
| pubmed-article:18212018 | lifeskim:mentions | umls-concept:C0687704 | lld:lifeskim |
| pubmed-article:18212018 | lifeskim:mentions | umls-concept:C1510827 | lld:lifeskim |
| pubmed-article:18212018 | lifeskim:mentions | umls-concept:C0679622 | lld:lifeskim |
| pubmed-article:18212018 | lifeskim:mentions | umls-concept:C0205314 | lld:lifeskim |
| pubmed-article:18212018 | lifeskim:mentions | umls-concept:C1511545 | lld:lifeskim |
| pubmed-article:18212018 | pubmed:issue | 9 | lld:pubmed |
| pubmed-article:18212018 | pubmed:dateCreated | 2008-4-10 | lld:pubmed |
| pubmed-article:18212018 | pubmed:abstractText | Troponin C (TnC) belongs to the superfamily of EF-hand (helix-loop-helix) Ca(2+)-binding proteins and is an essential component of the regulatory thin filament complex. In a patient diagnosed with idiopathic dilated cardiomyopathy, we identified two novel missense mutations localized in the regulatory Ca(2+)-binding Site II of TnC, TnC((E59D,D75Y)). Expression of recombinant TnC((E59D,D75Y)) in isolated rat cardiomyocytes induced a marked decrease in contractility despite normal intracellular calcium homeostasis in intact cardiomyocytes and resulted in impaired myofilament calcium responsiveness in Triton-permeabilized cardiomyocytes. Expression of the individual mutants in cardiomyocytes showed that TnC(D75Y) was able to recapitulate the TnC((E59D,D75Y)) phenotype, whereas TnC(E59D) was functionally benign. Force-pCa relationships in TnC((E59D,D75Y)) reconstituted rabbit psoas fibers and fluorescence spectroscopy of TnC((E59D,D75Y)) labeled with 2-[(4'-iodoacetamide)-aniline]naphthalene-6-sulfonic acid showed a decrease in myofilament Ca(2+) sensitivity and Ca(2+) binding affinity, respectively. Furthermore, computational analysis of TnC showed the Ca(2+)-binding pocket as an active region of concerted motions, which are decreased markedly by mutation D75Y. We conclude that D75Y interferes with proper concerted motions within the regulatory Ca(2+)-binding pocket of TnC that hinders the relay of the thin filament calcium signal, thereby providing a primary stimulus for impaired cardiomyocyte contractility. This in turn may trigger pathways leading to aberrant ventricular remodeling and ultimately a dilated cardiomyopathy phenotype. | lld:pubmed |
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| pubmed-article:18212018 | pubmed:language | eng | lld:pubmed |
| pubmed-article:18212018 | pubmed:journal | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:18212018 | pubmed:citationSubset | IM | lld:pubmed |
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| pubmed-article:18212018 | pubmed:status | MEDLINE | lld:pubmed |
| pubmed-article:18212018 | pubmed:month | May | lld:pubmed |
| pubmed-article:18212018 | pubmed:issn | 1542-0086 | lld:pubmed |
| pubmed-article:18212018 | pubmed:author | pubmed-author:GwathmeyJudit... | lld:pubmed |
| pubmed-article:18212018 | pubmed:author | pubmed-author:HajjarRoger... | lld:pubmed |
| pubmed-article:18212018 | pubmed:author | pubmed-author:CostelloCathe... | lld:pubmed |
| pubmed-article:18212018 | pubmed:author | pubmed-author:PimentelDavid... | lld:pubmed |
| pubmed-article:18212018 | pubmed:author | pubmed-author:BergEric AEA | lld:pubmed |
| pubmed-article:18212018 | pubmed:author | pubmed-author:HuoShuanghong... | lld:pubmed |
| pubmed-article:18212018 | pubmed:author | pubmed-author:LiaoRonglihR | lld:pubmed |
| pubmed-article:18212018 | pubmed:author | pubmed-author:WangChien-Kao... | lld:pubmed |
| pubmed-article:18212018 | pubmed:author | pubmed-author:LimChee... | lld:pubmed |
| pubmed-article:18212018 | pubmed:author | pubmed-author:HelmesMichiel... | lld:pubmed |
| pubmed-article:18212018 | pubmed:author | pubmed-author:YangMingfengM | lld:pubmed |
| pubmed-article:18212018 | pubmed:author | pubmed-author:YangHaijunH | lld:pubmed |
| pubmed-article:18212018 | pubmed:author | pubmed-author:ShiJianruJ | lld:pubmed |
| pubmed-article:18212018 | pubmed:issnType | Electronic | lld:pubmed |
| pubmed-article:18212018 | pubmed:day | 1 | lld:pubmed |
| pubmed-article:18212018 | pubmed:volume | 94 | lld:pubmed |
| pubmed-article:18212018 | pubmed:owner | NLM | lld:pubmed |
| pubmed-article:18212018 | pubmed:authorsComplete | Y | lld:pubmed |
| pubmed-article:18212018 | pubmed:pagination | 3577-89 | lld:pubmed |
| pubmed-article:18212018 | pubmed:dateRevised | 2011-11-17 | lld:pubmed |
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