Membrane hyperpolarization triggers myogenin and myocyte enhancer factor-2 expression during human myoblast differentiation.
It is widely thought that myogenin is one of the earliest detectable markers of skeletal muscle differentiation. Here we show that, during human myoblast differentiation, an inward rectifier K(+) channel (Kir2.1) and its associated hyperpolarization trigger expression and activity of the myogenic transcription factors, myogenin and myocyte enhancer factor-2 (MEF2). Furthermore, Kir2.1 current precedes and is required for the developmental increase in expression/activity of myogenin and MEF2. Drugs or antisense reducing Kir2.1 current diminished or suppressed fusion as well as expression/activity of myogenin and MEF2. In contrast, LY294002, an inhibitor of phosphatidylinositol 3-kinase (a pathway controlling initiation of the myogenic program) that inhibited both myogenin/MEF2 expression and fusion, did not affect Kir2.1 current. This non-blockade by LY294002 indicates that Kir2.1 acts upstream of myogenin and MEF2. We propose that Kir2.1 channel activation is a required key early event that initiates myogenesis by turning on myogenin and MEF2 transcription factors via a hyperpolarization-activated Ca(2+)-dependent pathway.
Konig
Stéphane
S
Département de Physiologie, Centre Médical Universitaire, Hôpital Cantonal Universitaire, 1 rue Michel-Servet, CH-1211 Geneva 4, Switzerland. Stephane.Konig@medecine.unige.ch
Hinard
Valérie
V
Arnaudeau
Serge
S
Holzer
Nicolas
N
Potter
Gaël
G
Bader
Charles R
CR
Bernheim
Laurent
L
D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D002138:Calibration; D002454:Cell Differentiation; D002455:Cell Division; D002462:Cell Membrane / Q000378:metabolism*; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000096:biosynthesis*; D004594:Electrophysiology; D017930:Genes, Reporter; D006801:Humans; D007150:Immunohistochemistry; D007477:Ions; D007700:Kinetics; D064326:MEF2 Transcription Factors; D008564:Membrane Potentials; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D009025:Morpholines / Q000494:pharmacology; D032446:Myoblasts / Q000378:metabolism*; D018006:Myogenic Regulatory Factors; D018008:Myogenin / Q000096:biosynthesis*; D016376:Oligonucleotides, Antisense / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D024661:Potassium Channels, Inwardly Rectifying / Q000378:metabolism; D013997:Time Factors; D014157:Transcription Factors / Q000096:biosynthesis*; D014158:Transcription, Genetic; D014162:Transfection
D002867:Chromones; D004268:DNA-Binding Proteins; D007477:Ions; D064326:MEF2 Transcription Factors; C503799:MYOG protein, human; D009025:Morpholines; D018006:Myogenic Regulatory Factors; D018008:Myogenin; D016376:Oligonucleotides, Antisense; D000081082:Phosphoinositide-3 Kinase Inhibitors; D024661:Potassium Channels, Inwardly Rectifying; D014157:Transcription Factors; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D002118:Calcium