Non-genomic mechanisms of progesterone action in the brain

Abstract

Progesterone is a gonadal steroid hormone whose physiological effects extend well beyond the strict confines of reproductive function. In fact, progesterone can have important effects on a variety of tissues, including the bone, the heart and the brain. Mechanistically, progesterone has been thought to exert its effects through the progesterone receptor (PR), a member of the nuclear steroid hormone superfamily, and as such, acts through specific progesterone response elements (PRE) within the promoter region of target genes to regulate transcription of such genes. This has been often described as the "genomic" mechanism of progesterone action. However, just as progesterone has a diverse range of tissue targets, the mechanisms through which progesterone elicits its effects are equally diverse. For example, progesterone can activate alternative receptors, such as membrane-associated PRs (distinct from the classical PR), to elicit the activation of several signaling pathways that in turn, can influence cell function. Here, we review various non-nuclear (i.e., non-genomic) signaling mechanisms that progesterone can recruit to elicit its effects, focusing our discussion primarily on those signaling mechanisms by which progesterone influences cell viability in the brain.

Keywords: brain; non-genomic; progesterone; progesterone receptor; signaling.

Figure 1

Mechanism of progesterone action in the brain. This figure provides a conceptual overview of how progesterone can elicit both genomic and non-genomic effects that impact its protective effects on the brain, and exemplifies how activation of complementary signaling cascades may be required for progesterone to fully elicit its effects. Using BDNF and two members of the ERK/MAPK family as paradigmatic examples of key mediators of progesterone-induced neuroprotection, this diagram underscores the fact that the protective effects of progesterone cannot be elicited by one signaling pathway alone, but rather, require complementary activation of multiple signaling pathways. In this example, the induction of BDNF synthesis requires the PR operating through its classical, genomic mechanism of action. However, such synthesis may not be meaningful unless the cellular content of BDNF can be secreted, leading in turn to the activation of its cognate receptors (ex. TrkB and/or p75) which can then elicit additional signaling pathways associated with cellular protection. This release of BDNF is mediated by a distinct receptor, Pgrmc1. In addition, other membrane-associated progesterone receptors, such as the mPR family of receptors, may elicit the activation of related signaling pathways that help finely regulate the process. In the example illustrated, activation of mPR may lead to activation of ERK1/2, which in turn, has been shown to exert an inhibitory influence on BDNF gene expression.