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Signaling Pathway for Endothelin-1- and Phenylephrine-Induced cAMP Response Element Binding Protein Activation in Rat Ventricular Myocytes: Role of Inositol 1,4,5-Trisphosphate Receptors and CaMKII.
Cell Physiol Biochem ; 41(1): 399-412, 2017.
Article em En | MEDLINE | ID: mdl-28214885
BACKGROUND/AIMS: Endothelin-1 (ET-1) and the α1-adrenoceptor agonist phenylephrine (PE) activate cAMP response element binding protein (CREB), a transcription factor implicated in cardiac hypertrophy. The signaling pathway involved in CREB activation by these hypertrophic stimuli is poorly understood. We examined signaling pathways for ET-1- or PE-induced cardiac CREB activation. METHODS: Western blotting was performed with pharmacological and genetic interventions in rat ventricular myocytes. RESULTS: ET-1 and PE increased CREB phosphorylation, which was inhibited by blockade of phospholipase C, the extracellular-signal-regulated kinase 1/2 (ERK1/2) pathway, protein kinase C (PKC) or Ca2+-calmodulin-dependent protein kinase II (CaMKII). Intracellular Ca2+ buffering decreased ET-1- and PE-induced CREB phosphorylation by ≥80%. Sarcoplasmic reticulum Ca2+ pump inhibitor, inositol 1,4,5-trisphosphate receptor (IP3R) blockers, or type 2 IP3R (IP3R2) knock-out abolished ET-1- or PE-induced CREB phosphorylation. ET-1 and PE increased phosphorylation of CaMKII and ERK1/2, which was eliminated by IP3R blockade/knock-out or PKC inhibition. Activation of CaMKII, but not ERK1/2, by these agonists was sensitive to Ca2+ buffering or to Gö6976, the inhibitor of Ca2+-dependent PKC and protein kinase D (PKD). CONCLUSION: CREB phosphorylation by ET-1 and PE may be mainly mediated by IP3R2/Ca2+-PKC-PKD-CaMKII signaling with a minor contribution by ERK1/2, linked to IP3R2 and Ca2+-independent PKC, in ventricular myocytes.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Fenilefrina / Transdução de Sinais / Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico / Endotelina-1 / Receptores de Inositol 1,4,5-Trifosfato / Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina Limite: Animals Idioma: En Ano de publicação: 2017 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Fenilefrina / Transdução de Sinais / Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico / Endotelina-1 / Receptores de Inositol 1,4,5-Trifosfato / Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina Limite: Animals Idioma: En Ano de publicação: 2017 Tipo de documento: Article