UC San Diego

GnRH differentially regulates the expression of LH[Beta] and FSH[Beta] in the same anterior pituitary gonadotrope cell. The mechanisms that allow gonadotrope cells to decode the GnRH signal are not well understood but it has been postulated that differential accumulation of secondary messengers cAMP and Ca²⁺ may play a role. Targets of cAMP in the gonadotropes have not been elucidated. Thus, studying cAMP signaling will provide insight into GnRH regulation of LH[Beta] and FSH[Beta]. cAMP is known to activate PKA. PKA is necessary for LH[Beta] and FSH[Beta] induction by GnRH, however, is only sufficient for FSH[Beta]. The only known target of PKA, CREB, does not play a role in FSH[Beta] induction. Moreover, PKA effect does not map to GnRH-regulated response elements on the FSH[Beta] promoter. Another hormone called PACAP is known to selectively increase intracellular cAMP. However, the response to PACAP maps to the GnRH responsive AP1 site of the FSH[Beta] promoter. PACAP can induce AP1 proteins, c-Fos and c-Jun, which are necessary for induction of FSH[Beta]. Induction of c-Fos by PACAP requires PKA, ERK1/2, and p38 MAPK pathways and maps to the SRF site, which is also necessary for induction by GnRH. PACAP activates ERK, which leads to the phosphorylation of ELK and its interaction with SRF. A dominant negative form of Epac, a novel cAMP target in the gonadotrope, can abrogate induction of c-Fos by PACAP, and thus Epac may bridge cAMP production to MAPK pathway activation, identifying a point of crosstalk between PACAP and GnRH signaling pathways