The calcineurin pathway links hyperpolarization (Kir2.1)-induced Ca2+ signals to human myoblast differentiation and fusion

• Published in: Development (Cambridge) Vol. 133; no. 16; pp. 3107 - 3114
• Main Authors: Konig, Stéphane, Béguet, Anne, Bader, Charles R, Bernheim, Laurent
• Format: Journal Article
• Language: English
• Published: England The Company of Biologists Limited 15.08.2006
• Subjects: Calcineurin - metabolism; Calcium Signaling; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Calcium-Calmodulin-Dependent Protein Kinases - metabolism; Cell Differentiation; Cell Fusion; Cell Membrane - metabolism; Cell Polarity; Humans; MEF2 Transcription Factors; Myoblasts - cytology; Myoblasts - metabolism; Myogenic Regulatory Factors - metabolism; Myogenin - metabolism; p38 Mitogen-Activated Protein Kinases - metabolism; Phosphatidylinositol 3-Kinases - metabolism; Potassium Channels, Inwardly Rectifying - metabolism
• ISSN: 0950-1991; 1477-9129
• DOI: 10.1242/dev.02479

In human myoblasts triggered to differentiate, a hyperpolarization, resulting from K + channel (Kir2.1) activation, allows the generation of an intracellular Ca 2+ signal. This signal induces an increase in expression/activity of two key transcription factors of the differentiation process, myogenin and MEF2. Blocking hyperpolarization inhibits myoblast differentiation. The link between hyperpolarization-induced Ca 2+ signals and the four main regulatory pathways involved in myoblast differentiation was the object of this study. Of the calcineurin, p38-MAPK, PI3K and CaMK pathways, only the calcineurin pathway was inhibited when Kir2.1-linked hyperpolarization was blocked. The CaMK pathway, although Ca 2+ dependent, is unaffected by changes in membrane potential or block of Kir2.1 channels. Concerning the p38-MAPK and PI3K pathways, their activity is present already in proliferating myoblasts and they are unaffected by hyperpolarization or Kir2.1 channel block. We conclude that the Kir2.1-induced hyperpolarization triggers human myoblast differentiation via the activation of the calcineurin pathway, which, in turn, induces expression/activity of myogenin and MEF2.