ACTH receptors are G-protein coupled receptors. Among the G proteins Gs and Gi2 are implicated in ACTH signaling. ACTH also increases the transcription of Galpha q and G alpha 11 which couple the ACTH receptor (39). Mutations of the alpha subunits of Gs and Gi2 are associated with adrenocortical tumor formation (40). Signals that initiate from the ACTH receptor and the G-proteins lead to cAMP formation and activation of PKA and PKC. As a result several intermediate molecules are involved including kinases and transcription factors that orchestrate the ACTH actions on adrenal cells.

SAPK and JNK: The ACTH receptor is a weak activator of MAP Kinases ERK1 and ERK2. Nevertheless, ERK1 and ERK2 activation is important in ACTH-triggered mitogenic effects (41). In normal adrenal cortical cells, ACTH-R signals lead to activation of the Stress Activated Protein Kinase (SAPK) JNK. Activation of JNK depends on PKC activity and mobilization of intracellular Ca++ implying that both PKC activation and Ca++ influx result from the binding of ACTH to its receptor (42).

Akt/PKB: In tissue culture experiments using the Y1 adrenocortical tumor cell line, ACTH exerts antiproliferative effect, mediated by cAMP. ACTH signals result in dephosphorylation and inactivation of Akt/PKB kinase thus inhibiting the proliferation of adrenocortical tumor cells (43). Such anti-proliferative effect is most likely associated with increased steroidogenesis and suppression of the malignant phenotype of this particular cell line.

CREM and CREB: The ACTH / MC2 receptor effects are mediated via activation of the cAMP pathway, which includes the cAMP-dependent transcription factors CREM (cAMP responsive element modulator) and CREB (cAMP responsive element binding protein) that result in transcriptional activation of steroidogenic enzymes, cell proliferation and differentiation (44).

AP-1: Activation of the ACTH receptor leads to stimulation of Fos and Jun transcription, which by heterodimerizing form the AP1 complex. It should be noted here that the Fos gene family consists of four members, c-Fos, FosB, Fra1 and Fra2 while the Jun family consists of three members, c-Jun, JunB and JunD. These proteins form hetero- or homo- dimers inducing transcription through binding to AP1- binding sites. Activation of AP1-dependent transcriptions leads to the production of several pro-mitotic proteins while its inhibition results in a blockade of cell cycle to the G1 to S phase transition.