| pubmed-article:18957419 | rdf:type | pubmed:Citation | lld:pubmed |
| pubmed-article:18957419 | lifeskim:mentions | umls-concept:C0018787 | lld:lifeskim |
| pubmed-article:18957419 | lifeskim:mentions | umls-concept:C0031727 | lld:lifeskim |
| pubmed-article:18957419 | lifeskim:mentions | umls-concept:C0033640 | lld:lifeskim |
| pubmed-article:18957419 | lifeskim:mentions | umls-concept:C0030685 | lld:lifeskim |
| pubmed-article:18957419 | lifeskim:mentions | umls-concept:C0596235 | lld:lifeskim |
| pubmed-article:18957419 | lifeskim:mentions | umls-concept:C0851285 | lld:lifeskim |
| pubmed-article:18957419 | lifeskim:mentions | umls-concept:C0680255 | lld:lifeskim |
| pubmed-article:18957419 | lifeskim:mentions | umls-concept:C0391871 | lld:lifeskim |
| pubmed-article:18957419 | lifeskim:mentions | umls-concept:C1283071 | lld:lifeskim |
| pubmed-article:18957419 | lifeskim:mentions | umls-concept:C1963578 | lld:lifeskim |
| pubmed-article:18957419 | lifeskim:mentions | umls-concept:C1879547 | lld:lifeskim |
| pubmed-article:18957419 | lifeskim:mentions | umls-concept:C0965282 | lld:lifeskim |
| pubmed-article:18957419 | pubmed:issue | 3 | lld:pubmed |
| pubmed-article:18957419 | pubmed:dateCreated | 2009-1-12 | lld:pubmed |
| pubmed-article:18957419 | pubmed:abstractText | Recently, we identified a novel signaling pathway involving Epac, Rap, and phospholipase C (PLC)epsilon that plays a critical role in maximal beta-adrenergic receptor (betaAR) stimulation of Ca2+-induced Ca2+ release (CICR) in cardiac myocytes. Here we demonstrate that PLCepsilon phosphatidylinositol 4,5-bisphosphate hydrolytic activity and PLCepsilon-stimulated Rap1 GEF activity are both required for PLCepsilon-mediated enhancement of sarcoplasmic reticulum Ca2+ release and that PLCepsilon significantly enhances Rap activation in response to betaAR stimulation in the heart. Downstream of PLCepsilon hydrolytic activity, pharmacological inhibition of PKC significantly inhibited both betaAR- and Epac-stimulated increases in CICR in PLCepsilon+/+ myocytes but had no effect in PLCepsilon-/- myocytes. betaAR and Epac activation caused membrane translocation of PKCepsilon in PLCepsilon+/+ but not PLCepsilon-/- myocytes and small interfering RNA-mediated PKCepsilon knockdown significantly inhibited both betaAR and Epac-mediated CICR enhancement. Further downstream, the Ca2+/calmodulin-dependent protein kinase II (CamKII) inhibitor, KN93, inhibited betaAR- and Epac-mediated CICR in PLCepsilon+/+ but not PLCepsilon-/- myocytes. Epac activation increased CamKII Thr286 phosphorylation and enhanced phosphorylation at CamKII phosphorylation sites on the ryanodine receptor (RyR2) (Ser2815) and phospholamban (Thr17) in a PKC-dependent manner. Perforated patch clamp experiments revealed that basal and betaAR-stimulated peak L-type current density are similar in PLCepsilon+/+ and PLCepsilon-/- myocytes suggesting that control of sarcoplasmic reticulum Ca2+ release, rather than Ca2+ influx through L-type Ca2+ channels, is the target of regulation of a novel signal transduction pathway involving sequential activation of Epac, PLCepsilon, PKCepsilon, and CamKII downstream of betaAR activation. | lld:pubmed |
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| pubmed-article:18957419 | pubmed:language | eng | lld:pubmed |
| pubmed-article:18957419 | pubmed:journal | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:18957419 | pubmed:citationSubset | IM | lld:pubmed |
| pubmed-article:18957419 | pubmed:chemical | http://linkedlifedata.com/r... | lld:pubmed |
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| pubmed-article:18957419 | pubmed:status | MEDLINE | lld:pubmed |
| pubmed-article:18957419 | pubmed:month | Jan | lld:pubmed |
| pubmed-article:18957419 | pubmed:issn | 0021-9258 | lld:pubmed |
| pubmed-article:18957419 | pubmed:author | pubmed-author:SmrckaAlan... | lld:pubmed |
| pubmed-article:18957419 | pubmed:author | pubmed-author:KelleyGrant... | lld:pubmed |
| pubmed-article:18957419 | pubmed:author | pubmed-author:DirksenRobert... | lld:pubmed |
| pubmed-article:18957419 | pubmed:author | pubmed-author:BlaxallBurns... | lld:pubmed |
| pubmed-article:18957419 | pubmed:author | pubmed-author:MalikSundeepS | lld:pubmed |
| pubmed-article:18957419 | pubmed:author | pubmed-author:GoonasekeraSa... | lld:pubmed |
| pubmed-article:18957419 | pubmed:author | pubmed-author:OestreichEmil... | lld:pubmed |
| pubmed-article:18957419 | pubmed:issnType | Print | lld:pubmed |
| pubmed-article:18957419 | pubmed:day | 16 | lld:pubmed |
| pubmed-article:18957419 | pubmed:volume | 284 | lld:pubmed |
| pubmed-article:18957419 | pubmed:owner | NLM | lld:pubmed |
| pubmed-article:18957419 | pubmed:authorsComplete | Y | lld:pubmed |
| pubmed-article:18957419 | pubmed:pagination | 1514-22 | lld:pubmed |
| pubmed-article:18957419 | pubmed:dateRevised | 2011-8-1 | lld:pubmed |
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