Figure 1.

A schematic representation of the cross-talk between extracellular and intracellular progesterone signaling pathways in female reproductive behavior. Classical mechanism of action by progesterone- and ring-A class of progestins, mediated by nuclear PRs, promotes interactions with coactivators, and plays a predominant role. Progesterone effects mediated by second messengers (cAMP, cGMP) and extranuclear signaling kinases (PKA, PKC, CaMKII), activates MAPK signal transduction cascade, phosphorylation of nuclear transcription factors (TFs), PRs/PR coactivators, and CREB. Progesterone and progestins, act via the Src kinase, interact with extranuclear PRs to activate MAPK cascade. Progesterone acting via the extranuclear PKA/MAPK/DARPP-32 pathway can cause a decrease in phosphatase activity and an increase in phosphorylation of PR and/or its coactivators. Mating stimuli (VCS) and dopamine D₁ agonist can stimulate PKA activation. D₁ agonist-stimulated PKA-mediated pathway phosphorylates DARPP-32, which inhibits PP1, leading to the activation of CREB/PR/coactivators. VCS-stimulated PKA activation can also interact with MAPK cascade. Neuropeptides, nucleotides, GnRH, and PGE₂ can act through various receptor- and/or second messengers (cAMP, cGMP, NO) and transmit signals to the nuclear PRs or other TFs. Interactions between the signal transduction pathways may serve as an amplification mechanism to converge on nuclear TFs and/or coactivators to regulate gene transcription and translation to facilitate female reproductive behavior.