Unbound MEDLINE

PKC-ε mediates multiple endothelin-1 actions on systolic Ca2+ and contractility in ventricular myocytes.

Abstract

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.

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  • Publisher Full Text

    • Authors

    Kang M, Chung KY

    Institution

    Molecular and Cellular Pharmacology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.

    Source

    Biochemical and biophysical research communications 423:3 2012 Jul 6 pg 600-5

    MeSH

    Animals
    Bacterial Proteins
    Calcium
    Cells, Cultured
    Endothelin-1
    Luminescent Proteins
    Male
    Myocardial Contraction
    Myocytes, Cardiac
    Protein Kinase C-epsilon
    Rats
    Rats, Sprague-Dawley
    Systole
    Ventricular Function

    Pub Type(s)

    Journal Article
    Research Support, N.I.H., Extramural

    Language

    eng

    PubMed ID

    22699119