IP3 dependent Ca2+ signals in muscle cells are involved in regulation of gene expression

Potassium depolarization of cultured muscle cells was employed to study cellular responses linked to calcium signaling. Events occurring after depolarization include i) A transient increase of the IP3 mass (2-10s); ii) A slow calcium transient (5 to 25s) that propagates as a low concentration wave along the myotube showing a distinct calcium transient at the level of cell nuclei. Due to the presence of IP3 receptors both in the SR (A-band region) and in the nuclear envelope, these two events appear to be related; iii) Phosphorylation of mitogen activated kinases (ERK 1/2) and of the transcription factor CREB (30 s-10 min), as well as expression of the early genes c-fos, c-jun and egr-1 mRNA (5-15 min). Several independent pieces of evidence, including results obtained using inhibitors specific for individual steps, allowed us to connect these in a sequential manner. As the same type of signaling cascade can be triggered by oxidants, neurotransmitters and hormones, the ensemble of results allows us to propose a general model to describe signaling events that link membrane stimulation to regulation of gene transcription in skeletal muscle cells.