FIG. 9.

A model depicting the proposed mechanisms through which GnRH derepresses the FSHβ gene in immature gonadotropes. (A) GnRH binds to its G-protein-coupled receptor resulting in Ca²⁺ influx and activation of calmodulin. The calmodulin activates CaMKI, which phosphorylates class IIa HDACs at the FSHβ and Nur77 gene promoters, causing their dissociation from the complex and nuclear export, likely as a result of their binding 14-3-3 proteins. This may be helped by calmodulin's competing with MEF2D for binding HDAC4, both of which are associated with both promoters. (B) The activation of calmodulin by GnRH also leads to an increase in calcineurin levels, which stimulates Nur77 expression, likely as has been shown in T cells, through dephosphorylation of NFAT, which allows NFAT to translocate into the nucleus and activate Nur77 gene transcription. At the same time, calcineurin likely activates Nur77 through its dephosphorylation. (C) The increase in active nonphosphorylated Nur77 then activates the FSHβ gene by facilitating the recruitment of coactivators, possibly together with MEF2D and additional transcription factors (speckled ovals) recruited as a result of activation of other GnRH signaling pathways.