PKC-ε mediates multiple endothelin-1 actions on systolic Ca2+ and contractility in ventricular myocytes
| Autor: | Ka Young Chung, Misuk Kang |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
Male
Myofilament medicine.medical_specialty Systole Biophysics Protein Kinase C-epsilon Biology Biochemistry Article Rats Sprague-Dawley Contractility Bacterial Proteins Internal medicine medicine Animals Ventricular Function Myocyte Myocytes Cardiac Molecular Biology Cells Cultured Protein kinase C Sarcolemma Endothelin-1 Cardiac muscle Cell Biology Myocardial Contraction Endothelin 1 Rats Luminescent Proteins medicine.anatomical_structure Endocrinology Calcium |
| Zdroj: | Biochemical and Biophysical Research Communications. 423:600-605 |
| ISSN: | 0006-291X |
| Popis: | Endothelin-1 (ET-1) induces positive inotropy (enhanced contractility) in cardiac muscle, but establishing underlying cellular mechanisms has been controversial in part because of a growing number of signaling pathways and end effectors targeted by ET-1. Here we present evidence that ET-1 induces positive inotropism in ventricular tissue by increasing both systolic Ca2+ and myofilament Ca2+ sensitivity. To examine the roles of PKC-δ and PKC-ε in these acute responses to ET-1, kinase inactive dominant negative PKC (dn-PKC) constructs were expressed in adult rat ventricular myocytes. Yellow fluorescent protein (YFP) was fused to dn-PKC constructs to visualize expression and localization of dn-PKC in living myocytes. Due to an alanine to glutamate mutation in the pseudosubstrate site, dn-PKCs constitutively translocated to anchoring sites and were unaffected by agonist or phorbol ester treatment. Dn-PKC-δ-YFP mainly distributed at Z-lines and at intercalated disks in adult myocytes, whereas dn-PKC-ε-YFP stained the surface sarcolemma, T-tubules/Z-lines and perinuclear region. Myocytes expressing dn-PKC-δ-YFP showed normal systolic Ca2+ and contractile responses to ET-1. In contrast, the entire ensemble of ET-1 responses was blocked in myocytes expressing dn-PKC-ε-YFP including increased Ca2+ transients, enhanced myofilament Ca2+ sensitivity, and positive inotropy. This report provides direct evidence that PKC-ε is activated early and robustly following ET-1 stimulation and thus mediates multiple intracellular changes underlying the acute actions of ET-1 on myocardium. |
| Databáze: | OpenAIRE |
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