Progesterone-Mediated Non-Classical Signaling

Progesterone is essential for pregnancy maintenance and menstrual cycle regulation. Hormone action has been primarily ascribed to the well-characterized classical signaling pathway involving ligand binding, activation of nuclear progesterone receptors (PRs), and subsequent activation of genes containing progesterone response elements (PREs). Recent studies have revealed progesterone actions via non-classical signaling pathways, often mediated by non-genomic signaling. Progesterone signaling, in conjunction with growth factor signaling, impacts on the function of growth factors and regulates important physiological actions such as cell growth and remodeling, as well as apoptosis. This review focuses on non-classical progesterone signaling pathways, both including and excluding PR, and highlights how research in this area will provide a better understanding of progesterone actions and may inform novel therapeutic strategies. Progesterone modulates a wide range of physiological processes through non-classical signaling pathways via various non-nuclear progesterone receptors including membrane-bound progesterone receptors, PGRMC1, and GABA-A receptors.Non-classical signaling includes growth receptor signaling pathways such as alterations in intracellular cAMP levels and modulation of CaMKII activity.Activation of tyrosine kinase SRC, the p44/p42 MAPK pathway, and p38 MAPK activation via progesterone are other non-classical signaling pathways.Recent discovery of integration of mechanical and endocrine signals during labor has emphasized the crucial role of non-classical progesterone actions.Remarkable progress in the identification of progesterone effects via non-classical signaling has provided a foundation upon which to develop new therapeutic targets for novel pharmacological interventions in diverse physiological processes.