Figure 6.

Excitation–transcription coupling. (1) InsP₃R-mediated cytosolic Ca²⁺ increase induces activation of different signaling pathways: (2) Ca²⁺ activates cytosolic and nuclear CaMKII that phosphorylates the inhibitory transcription factor histone deacetylase (HDAC) and (3) induces its export out of the nucleus. (4) MEF2 is activated and this triggers hypertrophic genes expression. (5) Ca²⁺ increases, including via InsP₃Rs, activates calcineurin (CnA), leading to dephosphorylation of nuclear factor of activated T-cells (NFAT) and its translocation to the nucleus. (6) NFAT then activates the transcription of hypertrophic genes including fetal genes (InsP₃R, NPPA, NPPB, RCAN1) and can also repress miR-133. (7) Nuclear Ca²⁺ signals arising from InsP₃R can contribute to activation of nuclear CnA and trigger pathways for hypertrophy (9). (7) miR-133 suppresses expression of NFAT, CnA, and InsP₃R, which will inhibit the hypertrophic responses previously described (8).