Elsevier

Reproductive Biology

Volume 13, Issue 4, December 2013, Pages 279-289
Reproductive Biology

Review Article
The putative roles of nuclear and membrane-bound progesterone receptors in the female reproductive tract☆

https://doi.org/10.1016/j.repbio.2013.09.001Get rights and content

Abstract

Progesterone produced by the corpus luteum (CL) is a key regulator of normal cyclical reproductive functions in the females of mammalian species. The physiological effects of progesterone are mediated by the canonical genomic pathway after binding of progesterone to its specific nuclear progesterone receptor (PGR), which acts as a ligand-activated transcription factor and has two main isoforms, PGRA and PGRB. These PGR isoforms play different roles in the cell; PGRB acts as an activator of progesterone-responsive genes, while PGRA can inhibit the activity of PGRB. The ratio of these isoforms changes during the estrous cycle and pregnancy, and it corresponds to the different levels of progesterone signaling occurring in the reproductive tract. Progesterone exerts its effects on cells also by a non-genomic mechanism by the interaction with the progesterone-binding membrane proteins including the progesterone membrane component (PGRMC) 1 and 2, and the membrane progestin receptors (mPRs). These receptors rapidly activate the appropriate intracellular signal transduction pathways, and subsequently they can initiate specific cell responses or modulate genomic cell responses. The diversity of progesterone receptors and their cellular actions enhances the role of progesterone as a factor regulating the function of the reproductive system and other organs. This paper deals with the possible involvement of nuclear and membrane-bound progesterone receptors in the function of target cells within the female reproductive tract.

Introduction

The main function of the corpus luteum (CL), formed from the cells of a ruptured Graafian follicle, is progesterone production. Progesterone multidirectional effects on the regulation of cyclic changes in the female reproductive tract and on the course of pregnancy are well known in both humans and animals [1]. Physiological effects of progesterone on target cells are achieved by binding to a specific nuclear progesterone receptor (PGR), the mechanism referred to as genomic pathway, or by binding to membrane non-genomic receptors (PGRMC and mPR). In the genomic pathway, cellular response occurs after a few hours, while the non-genomic pathway elicits a cell response after minutes or even seconds. In this paper, the recent data on nuclear and membrane-bound progesterone receptors and the possible involvement of progesterone signaling in the function of the target cells in the female reproductive tract are discussed.

Section snippets

Structure and physiological properties of PGR

PGR protein expression has been found in human ovary [2], uterus [3], testis [4], brain [5], pancreas [6], bone [7], mammary gland [8] and urinary tract [9]. There exist two main isoforms of this receptor, A (PGRA) and B (PGRB), whose presence and actions have been demonstrated in humans and other species [10], [11], [12], [13], [14]. This receptor, along with the receptors for estradiol, mineralocorticoids, glucocorticoids and androgens, belongs to the superfamily of nuclear receptors. Similar

Activation of PGR

The inactive form of the PGR receptor is located in the cytosol and is bound to a complex of chaperone proteins, including HSP 90 and HSP 70, p23 and immunophilins [29]. The receptor-chaperone protein complex provides a specific conformation of the receptor that permits the proper ligand binding. Binding of progesterone to the LBD initiates a number of conformational changes, disassociation of the chaperone proteins and nuclear translocation of PGR (Fig. 2) [30]. In the nucleus, receptors

Regulation of PGR transcriptional activity

Binding of PGR to the HRE is followed by the recruitment of co-regulators. These molecules participate in the regulation of the target gene transcription. Co-regulators, which can be either co-activators or co-repressors, interact with the protein-receptor complex within the AF-2 domain of the receptor and do not bind to the DNA sequence [31]. Some of the co-activators are epigenetically regulated by histone acetylation, which results in the re-arrangement of the chromatin. This results in the

Physiological role of PGRA and PGRB isoforms

It is not feasible to directly determine the PGRA mRNA level because its whole sequence is a part of the PGRB mRNA. Therefore, the amount of PGRA mRNA can only be determined by subtracting the level of PGRB mRNA from the total amount of mRNA for PGR. The highest level of PGRB mRNA in the human [40] and bovine [41] corpus luteum (CL) is found at the beginning of the ovarian cycle and thereafter it gradually declines. The profile of cyclic PGRA mRNA expression was very similar to that for PGRB

The effects of non-genomic progesterone signaling in the cell

Progesterone can also affect the cell by a non-genomic mechanism, in which the effect of the hormone is observed after a very short time following its experimental application (i.e., several seconds or minutes) and are not delayed by the inhibitors of transcription or translation [43], [44], [45]. This non-genomic action of progesterone has been demonstrated in various organs and tissues, including the female reproductive tract from different species [45], [46], [47], [48]. Bovine reproductive

PGRMC 1 and 2 – structure, expression and functions

PGRMC1 and PGRMC2 proteins belong to a family of membrane-associated progesterone receptor (MAPR) proteins [45], [46]. PGRMC1 protein was first isolated from the porcine vascular smooth muscle cells [60]. The protein is composed of 194 amino acids [60] with a molecular weight of 28 kDa [44] and is localized mainly in the cell membrane [44], [61], [62], [63]. It is also expressed in the endoplasmic reticulum and Golgi apparatus [44], [60], [64]. PGRMC1 contains a short N-terminal extracellular

Membrane progestin receptors (mPRs) – structure and function

The non-genomic effects of progesterone on target cells may also be mediated by its binding to membrane receptors (mPRs), belonging to the PAQR family of proteins, which were first isolated from the spotted sea trout ovary [85]. The presence of these proteins was also demonstrated in the female reproductive tract tissues in humans [86], [87], swine [88], mice [89], sheep [90], [91] and rats [68]. In humans and other vertebrates, three isoforms of the receptor have been identified, encoded by

The hypothetical role of membrane-bound progesterone receptors

The presence of membrane proteins that bind progesterone ensures the generation of a more rapid cellular response as compared with the genomic responses to the steroid. This allows the target cells to respond quickly to the changes in the hormonal milieu and modulate the cell response elicited by the signals that activate the genomic signaling pathway. In a recent study in cattle, the highest mRNA expression of PGRMC1, PGRMC2 and SERBP1 in the endometrium [55] and PGRMC1 and SERBP1 in the

Future perspectives

The presence of several isoforms of PGR and membrane-binding proteins in the target cell suggests the existence of an array of cellular responses to progesterone. The best way to corroborate the exact physiological significance of all of the progesterone signaling pathways would be a selective activation or blockade of the receptor or its activity. However, at present there are no known selective activators of the expression of the progesterone receptor protein, and only AG-205 is known to

Conflict of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the article reported.

Acknowledgements

The authors’ research was supported by the National Science Centre (2012/05/B/NZ4/01810) the Ministry of Science and Higher Education (N311 113638) and the Polish Academy of Sciences.

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      Our previous studies confirmed the nongenomic action of P4 on the secretory function of the bovine uterus [13–15]. Moreover, we observed variable mRNA and protein expression for PGRMC1, PGRMC2 and its binding partner SERPINE1 mRNA-binding protein (SERBP1) in the bovine endometrium [7] and myometrium [6] during the oestrous cycle and the first trimester of pregnancy in cows, indicating that PGRMC receptors or the PGRMC1/SERBP1 protein complex participate in regulating uterine cell function in cows [6,7,16]. SERBP1, also known as plasminogen activator inhibitor 1 RNA-binding protein (PAIRBP1), may create a complex with PGRMC1 and mediates the responsiveness to P4 via PGRMC1 [17].

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    ☆

    The material described in this review article was presented as an invited lecture at Ludwig Fraenkel Symposium “Endocrine Control of Corpus Luteum Function” in Wrocław, Poland (5–6 September, 2013).

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    Copyright © 2013 Society for Biology of Reproduction & the Institute of Animal Reproduction and Food Research of Polish Academy of Sciences in Olsztyn. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.