Membrane Progesterone Receptors (mPRs, PAQRs): Review of Structural and Signaling Characteristics

Abstract

The role of membrane progesterone receptors (mPRs), which belong to the progestin and adipoQ receptor (PAQR) family, in mediating rapid, nongenomic (non-classical) progestogen actions has been extensively studied since their identification 20 years ago. Although the mPRs have been implicated in progestogen regulation of numerous reproductive and non-reproductive functions in vertebrates, several critical aspects of their structure and signaling functions have been unresolved until recently and remain the subject of considerable debate. This paper briefly reviews recent developments in our understanding of the structure and functional characteristics of mPRs. The proposed membrane topology of mPRα, the structure of its ligand-binding site, and the binding affinities of steroids were predicted from homology modeling based on the structures of other PAQRs, adiponectin receptors, and confirmed by mutational analysis and ligand-binding assays. Extensive data demonstrating that mPR-dependent progestogen regulation of intracellular signaling through mPRs is mediated by activation of G proteins are reviewed. Close association of mPRα with progesterone membrane receptor component 1 (PGRMC1), its role as an adaptor protein to mediate cell-surface expression of mPRα and mPRα-dependent progestogen signaling has been demonstrated in several vertebrate models. In addition, evidence is presented that mPRs can regulate the activity of other hormone receptors.

Keywords: 2nd messengers; G-protein; PAQR7; PGRMC1; ligand-binding domain; mPRα; modeling.

Figure 1

In situ proximity ligation analysis (PLA) of the interactions of mPRα with an inhibitory G protein (G_i) using specific mPRα and G_iα-subunit antibodies in human vascular smooth muscle cells (VSMCs). (A) A close association (distance < 40 nm) between mPRα and G_i is shown by the presence of red dots in the image, which had been preincubated with inactivated pertussis toxin (iPTX). (B) The PLA image shows a marked decrease in the number of red dots in VSMCs that had been pretreated with activated pertussis toxin (aPTX). Treatment with aPTX uncouples G_i from hormone receptors, whereas iPTX is inactive. Nuclei are stained blue with DAPI. Reproduced from Pang and Thomas [48] with permission.

Figure 2

In situ proximity ligation analysis (PLA) of the association of mPRα with a PGRMC1 in zebrafish oocytes using zebrafish mPRα and PGRMC1 (PG) antibodies. (A) Close proximity of mPRα and PGRMC1 (<40 nm) in the image are shown as red dots. (B) PLA using the PGRMC1 antibody and IgG as a negative control showing the absence of red dots in the image. The nuclei (blue) of the follicle cells surrounding the oocyte are stained with DAPI. Scale bar 100 µm. Produced from Aizen et al. [34] with permission.

Figure 3

Current model of mPRα association with adaptor and G proteins, regulation of second messenger pathways (black), and regulation of other receptors (red). Hatched lines indicate intermediates/mechanisms of receptor regulation unknown. PG-PGRMC1—allo-allopregnanolone.