Homer modulates NFAT-dependent signaling during muscle differentiation.
While changes in intracellular calcium are well known to influence muscle contraction through excitation contraction coupling, little is understood of the calcium signaling events regulating gene expression through the calcineurin/NFAT pathway in muscle. Here, we demonstrate that Ca(+2) released via the inositol trisphosphate receptor (IP3R) increases nuclear entry of NFAT in undifferentiated skeletal myoblasts, but the IP3R Ca(+2) pool in differentiated myotubes promotes nuclear exit of NFAT despite a comparable quantitative change in [Ca(+2)]i. In contrast, Ca(+2) released via ryanodine receptors (RYR) increases NFAT nuclear entry in myotubes. The scaffolding protein Homer, known to interact with both IP3R and RYR, is expressed as part of the myogenic differentiation program and enhances NFAT-dependent signaling by increasing RYR Ca(+2) release. These results demonstrate that differentiated skeletal myotubes employ discrete pools of intracellular calcium to restrain (IP3R pool) or activate (RYR pool) NFAT-dependent signaling, in a manner distinct from undifferentiated myoblasts. The selective expression of Homer proteins contributes to these differentiation-dependent features of calcium signaling.
Stiber
Jonathan A
JA
Department of Medicine, Duke University, 4321 Medical Park Drive, Suite 200, Durham, NC 27704, USA.
Tabatabaei
Niloufar
N
Hawkins
April F
AF
Hawke
Thomas
T
Worley
Paul F
PF
Williams
R Sanders
RS
Rosenberg
Paul
P
D021581:Active Transport, Cell Nucleus; D000818:Animals; D000831:Animals, Newborn; D002110:Caffeine; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism; D020013:Calcium Signaling; D002352:Carrier Proteins / Q000502:physiology*; D002454:Cell Differentiation / Q000502:physiology*; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000378:metabolism; D000072233:Homer Scaffolding Proteins; D053496:Inositol 1,4,5-Trisphosphate Receptors; D051379:Mice; D018345:Mice, Knockout; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000378:metabolism; D018482:Muscle, Skeletal / Q000196:embryology / Q000254:growth & development / Q000378:metabolism; D032446:Myoblasts / Q000166:cytology* / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000378:metabolism / Q000502:physiology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism
D015220:Calcium Channels; D002352:Carrier Proteins; D000072233:Homer Scaffolding Proteins; D053496:Inositol 1,4,5-Trisphosphate Receptors; D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; D018160:Receptors, Cytoplasmic and Nuclear; D019837:Ryanodine Receptor Calcium Release Channel; D002110:Caffeine; D002118:Calcium