Original Research ArticleExpression of progesterone receptor membrane component (PGRMC) 1 and 2, serpine mRNA binding protein 1 (SERBP1) and nuclear progesterone receptor (PGR) in the bovine endometrium during the estrous cycle and the first trimester of pregnancy
Introduction
Progesterone (P4), produced in the corpus luteum (CL), regulates the timing of the estrous cycle and pregnancy in domestic animals, including cows [1]. This hormone affects endometrial development and facilitates blastocyst implantation within the uterus and during fetal development and maintenance of pregnancy [2]. In the uterus, the physiological effect of P4 is mediated by its interaction with a specific nuclear progesterone receptor (PGR), which has been identified as a ligand-activated transcription factor [3]. This receptor has several isoforms; however, the PGR-A and PGR-B isoforms, which arise from a single gene and are under control of different promoters [3], [4], are the most often studied. In humans, PGR-A (94 kDa) differs from PGR-B (120 kDa) in that it lacks 164-amino acids at the N-terminus [4]. These receptor isoforms having a similar molecular mass, were found in the cells of the bovine oviduct [5], mammary gland [6] and corpus luteum [7].
However, not all of the actions of P4 are mediated through its interaction with PGRs [8], [9]. It is now clear that P4 can also affect target cells through a rapid, nongenomic mechanism via novel membrane receptors with P4 binding activity, referred to as progesterone receptor membrane component (PGRMC) 1 and PGRMC2 [8], [9]. PGRMC1 is a small, 24–28 kDa protein possessing a single transmembrane domain and a cytoplasmic domain containing a cytochrome P450 b5/heme binding region [8], [9], [10]. It was recently demonstrated that PGRMC1 can associate with another polypeptide, termed serpine 1 mRNA binding protein (SERBP1; earlier called PAIRBP1), and that these two proteins form a membrane complex that binds P4 [8], [11], [12]. Activation of this complex by P4 causes an increase of cAMP levels and activation of protein kinase G, which leads to the reduction of Ca2+ levels in the cell [13], [14]. It has been found that the PGRMC1:SERBP1 complex mediates the anti-apoptotic effect of P4 in the ovary [13], [14], [15], and it regulates steroidogenesis and cellular homeostasis [10], [16], [17]. Much less data are available on PGRMC2; its mRNA/protein expression was detected previously in murine [18] and macaque [19] endometrium. Moreover, it was found that PGRMC2 may be involved in oviduct function [20], preterm labour [21] and carcinogenesis [22] and PGRMC2 mRNA level was positively correlated with estrogen receptor α (ESRα) [22].
In earlier studies we have shown that P4 decreased intracellular Ca2+ mobilization in bovine endometrial cells [23] and it inhibited oxytocin (OT)- stimulated PGF2α secretion from these cells, by both genomic and nongenomic pathway [24]. So it can be assumed that the latter effect of P4 was evoked partly via a membrane progesterone receptor – PGRMC1 found in the bovine endometrial cells [24] and in mouse and human endometrium [18]. However, there is limited data on the expression of PGRMC2 and SERBP1 in bovine endometrium during the estrous cycle and pregnancy. Since P4 is essentially involved in the control of uterine growth and cell differentiation, therefore the aim of the present study was to determine PGRMC1, PGRMC2, SERBP1 and PGR mRNA and protein expression in the bovine endometrium throughout the estrous cycle and during the first trimester of pregnancy.
Section snippets
Tissue collection
All experiments were performed in accordance with the principles and procedures of Animal Ethics Committee, University of Warmia and Mazury, Olsztyn. Uteri (ipsilateral to the ovary with a CL) from the healthy mature cows (4–7 years old) were collected at a commercial slaughterhouse on days 1–5, 6–10, 11–16, 17–20 (n = 6 per stage) of the estrous cycle and during weeks 3–5, 6–8 and 9–12 (n = 5 per stage) of pregnancy within 20 min of killing the animals. Days of the estrous cycle were assessed by
Expression of PGRMC1, PGRMC2, SERBP1 and PGR mRNA in the bovine endometrium
There were no significant differences (P > 0.05) in the PGRMC1 (Fig. 1a) and PGRMC2 (Fig. 1b) mRNA expression throughout the estrous cycle; however, the higher expression (P < 0.001) of these genes was detected in pregnant compared to cyclic animals (Fig. 1a, b). SERBP1 mRNA expression was the highest during days 11–16 of the estrous cycle and differed (P < 0.05) from mRNA expression on days 1–5 of the cycle (Fig. 1c). No significant variations in SERBP1 mRNA expression were observed during pregnancy
Discussion
The present study shows that mRNA and protein for the putative P4 membrane protein receptor PGRMC1, PGRMC2 and PGRMC1 binding partner – SERBP1, as well as nuclear PGR-A and PGR-B are expressed in the bovine endometrium during the estrous cycle and the first trimester of pregnancy. mRNA level of PGRMC1 and PGRMC2 remained relatively constant during the estrous cycle, and it significantly increased during gestation. However, protein expression of PGRMC1 and PGRMC2 did not increase in accordance
Acknowledgments
We thank Professor S. Okrasa (University of Warmia and Mazury, Olsztyn, Poland) for progesterone antiserum and Professor M. Wehling (Clinical Pharmacology Mannheim, University of Heidelberg, Mannheim, Germany) for PGRMC1 antibodies. This research was supported by the Ministry of Science and Higher Education (grant NN 311 348237), by the Foundation for Polish Science (PARENT-BRIDGE Programme - support for women, POMOST_C/37) and by the Polish Academy of Sciences. Part of this work was presented
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