Progestin receptor subtypes in the brain: the known and the unknown

Abstract

Progesterone (P), the most biologically active progestin of ovarian origin, modulates numerous cellular functions in the central nervous system to coordinate physiology and reproduction. The neurobiological activity of P is mediated not by a single form of the progestin receptor (PR), but by two neural isoforms of PRs, PR-A and PR-B. Classical model of P action assumes that these neural effects are primarily mediated via their intracellular PRs, acting as transcriptional regulators, in steroid-sensitive neurons, modulating genes and genomic networks. Evidence has emerged, however, that activation of neural PRs is much more diverse; four distinct classes of molecules, neurotransmitters, peptide growth factors, cyclic nucleotides, and neurosteroids have been shown to activate the PRs via cross-talk and pathway convergence. In addition, rapid signaling events associated with membrane receptors and/or subpopulations of cytoplasmic PRs, via activation of protein kinase cascades, regulate PR gene expression in the cytoplasm independent of PR nuclear action. The increasing in vitro and in vivo evidence of differential transcriptional activities and coregulator interactions between PR-A and PR-B predict that these isoforms could have distinct roles in mediating additional and/or alternate signaling pathways within steroid-sensitive neurons. In this minireview, we evaluate the available data and discuss the possible roles of the isoforms in the regulation of neurobiological processes.

Figure 1

Structural organization of PR isoforms. The numbers in the N-terminal region denote the amino acid position in each isoform. AF1, AF2, and AF3 are the activation function domains; H is the hinge region. The sequences important for dimerization and the first and second zinc finger regions of DBD are represented.

Figure 2

Schematic representation of integrated PR activation. Unliganded PR is present as an inactive complex associated with heat-shock proteins (HSP) and chaperone proteins (p29, p56). In the classical ligand-dependent pathway, P and other progestins bind to the PR, resulting in conformational change, dissociation of HSP and chaperone proteins, dimerization of the receptor, and binding to the hormone response element (HRE) in the target DNA. The P-induced conformational change facilitates the recruitment of cofactors and other general transcription factors (GTFs) to the promoter, producing a transcriptionally active complex that can direct gene transcription. Compounds such as cyclic nucleotides, neurotransmitters (NTs), growth factors (GFs), neurosteroids, and other environmental signals can activate second messengers and protein kinase pathways to activate PR and/or coactivators in a ligand-independent manner. Depending upon the activating stimulus, PRs can dimerize as homodimers (A:A, B:B) or heterodimers (A:B) and upon binding to HRE can recruit distinct sets of coactivators, leading to transcriptional activation of distinct subsets of genes.