Open Pharmaceutical Sciences Journal


ISSN: 1874-8449 ― Volume 4, 2017

New Insight into Progesterone-dependent Signalization



Karolina Kociszewska1, 2, Piotr Czekaj3, *
1 Students Scientific Society, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland
2 Department of Cardiosurgery, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland
3 Department of Cytophysiology, Chair of Histology and Embryology, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland

Abstract

Background:

Various effects of steroid hormone activity cannot easily be explained by the action of classical nuclear receptors and genomic signal transduction pathways. These activities are manifested principally as rapid processes, lasting from seconds to minutes, resulting in changes in ion transduction, calcium intracellular concentration, and level of the second messengers, which cannot be realized through the genomic pathway. Hence, it has been proposed that other kinds of mediators should be involved in steroid-induced processes, namely receptors located on the cell surface. The search for their chemical nature and role is of utmost importance. Current state of knowledge confirms their relation to GPCRs. Moreover, it seems that almost every nuclear receptor specific for steroid hormone family has its membrane-bound equivalent.

Objective:

In this review, we summarize current state of knowledge about nuclear and membrane receptors for progesterone, and describe their potential functions alone, as well as in cooperation with other receptors.

Conclusion:

In the light of common expression, both in species and organs, membrane receptors could play a role that is at least comparable to nuclear receptors. Further exploration of membrane receptor-dependent signaling pathways could give a new insight in the treatment of many endocrine and oncological pathologies.

Keywords: Progesterone, Nuclear progesterone receptors, Membrane progesterone receptors, PGRMC1, Classical and non-classical signaling pathways.


Article Information


Identifiers and Pagination:

Year: 2017
Volume: 4
First Page: 11
Last Page: 22
Publisher Id: PHARMSCI-4-11
DOI: 10.2174/1874844901704010011

Article History:

Received Date: 11/11/2016
Revision Received Date: 09/12/2016
Acceptance Date: 12/12/2016
Electronic publication date: 16/02/2017
Collection year: 2017

© 2017 Kociszewska and Czekaj

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: https://creativecommons.org/licenses/by/4.0/legalcode. This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


* Address correspondence to this author at the Department of Cytophysiology, Chair of Histology and Embryology, School of Medicine in Katowice, Medical University of Silesia, Medyków 18 str., 40-752 Katowice, Poland; Tel: +48 32 2088374; Fax: +48 32 2526574; E-mail: pcz@sum.edu.pl




1. INTRODUCTION

Progesterone (P4) is a 21-carbon steroid belonging to the family of pogestagens. It is synhesized in the corpus luteum, placenta, brain and adrenal gland. The nuclear progesterone receptor (nPR) with a gene located on chromosome 11 (11q13) is considered as a main target for P4. Its expression fluctuates in the ovary and endometrial layer of uterus during either physiologic and pathologic states [1Hammes SR, Levin ER. Minireview: Recent advances in extranuclear steroid receptor actions. Endocrinology 2011; 152(12): 4489-95.
[http://dx.doi.org/10.1210/en.2011-1470] [PMID: 22028449]
-3Sleiter N, Pang Y, Park C, et al. Progesterone receptor A (PRA) and PRB-independent effects of progesterone on gonadotropin-releasing hormone release. Endocrinology 2009; 150(8): 3833-44.
[http://dx.doi.org/10.1210/en.2008-0774] [PMID: 19423765]
]. The role of nuclear receptors for progesterone and other steroids, as well as molecular pathway mediated by them are widely recognized and achieved a significant position in the clinical practice [1Hammes SR, Levin ER. Minireview: Recent advances in extranuclear steroid receptor actions. Endocrinology 2011; 152(12): 4489-95.
[http://dx.doi.org/10.1210/en.2011-1470] [PMID: 22028449]
, 2Intlekofer KA, Petersen SL. Distribution of mRNAs encoding classical progestin receptor, progesterone membrane components 1 and 2, serpine mRNA binding protein 1, and progestin and ADIPOQ receptor family members 7 and 8 in rat forebrain. Neuroscience 2011; 172: 55-65.
[http://dx.doi.org/10.1016/j.neuroscience.2010.10.051] [PMID: 20977928]
]. However there still exist some effects controlled by steroid hormones, which could not be easily explained with the activity of classical, genomic pathway. These effects apear in the course of shorter period of time and take place in different cells and tissues. Thus, it has been suggested that P4 could act through extragenomic, non-classical pathways with crucial role of membrane receptors [2Intlekofer KA, Petersen SL. Distribution of mRNAs encoding classical progestin receptor, progesterone membrane components 1 and 2, serpine mRNA binding protein 1, and progestin and ADIPOQ receptor family members 7 and 8 in rat forebrain. Neuroscience 2011; 172: 55-65.
[http://dx.doi.org/10.1016/j.neuroscience.2010.10.051] [PMID: 20977928]
]. Besides PR, also other steroid hormone receptors can be localized in cell membrane. A number of non-genomic pathways dependent on membrane receptors, with characteristic rapid effects, i.e. the influence of estrogens on neurons, testosterone on macrophages and prostate cells, as well as the activity of glucocorticosteroids, aldosterone, triiodothyronine, thyroxine, retinoids and calcitriol, have been described [4Losel RM, Falkenstein E, Feuring M, et al. Nongenomic steroid action: controversies, questions, and answers. Physiol Rev 2003; 83(3): 965-1016.
[http://dx.doi.org/10.1152/physrev.00003.2003] [PMID: 12843413]
-7Wendler A, Albrecht C, Wehling M. Nongenomic actions of aldosterone and progesterone revisited. Steroids 2012; 77(10): 1002-6.
[http://dx.doi.org/10.1016/j.steroids.2011.12.023] [PMID: 22285849]
]. Membrane receptors seem to be specific variants of nuclear receptors and are formed through alternative splicing or post-translational modification [8Ahmad N, Kumar R. Steroid hormone receptors in cancer development: a target for cancer therapeutics. Cancer Lett 2011; 300(1): 1-9.
[http://dx.doi.org/10.1016/j.canlet.2010.09.008] [PMID: 20926181]
].

2. GENOMIC PATHWAY

Classical receptors for P4 belong to the superfamily of nuclear receptors, which comprises also receptors for other steroids, thyroid hormones, retinoic acid and vitamin D, as well as the so-called ‘small receptors’, for instance the farnesoid X receptor (FXR), which binds bile acids, or the peroxisome proliferator activated receptor (PPAR), responsible for carbohydrate-lipid homeostasis [4Losel RM, Falkenstein E, Feuring M, et al. Nongenomic steroid action: controversies, questions, and answers. Physiol Rev 2003; 83(3): 965-1016.
[http://dx.doi.org/10.1152/physrev.00003.2003] [PMID: 12843413]
, 9Kastner P, Krust A, Turcotte B, et al. Two distinct estrogen-regulated promoters generate transcripts encoding the two functionally different human progesterone receptor forms A and B. EMBO J 1990; 9(5): 1603-14.
[PMID: 2328727]
]. Proper ligands for many of these receptors were not recognized, hence they were called the ‘orphan receptors’ [4Losel RM, Falkenstein E, Feuring M, et al. Nongenomic steroid action: controversies, questions, and answers. Physiol Rev 2003; 83(3): 965-1016.
[http://dx.doi.org/10.1152/physrev.00003.2003] [PMID: 12843413]
]. Currently, they are known to act as ligand-dependent transcriptional factors which regulate numerous physiologic processes through binding with specific hormone response element (HRE) sequences of the target genes [10Chalbos D, Galtier F. Differential effect of forms A and B of human progesterone receptor on estradiol-dependent transcription. J Biol Chem 1994; 269(37): 23007-12.
[PMID: 8083200]
, 11Kraus WL, Montano MM, Katzenellenbogen BS. Identification of multiple, widely spaced estrogen-responsive regions in the rat progesterone receptor gene. Mol Endocrinol 1994; 8(8): 952-69.
[PMID: 7997237]
].

Two basic receptor isoforms are nPRA and nPRB, encoded by the same gene but characterized by distinct initiation sites of translation [9Kastner P, Krust A, Turcotte B, et al. Two distinct estrogen-regulated promoters generate transcripts encoding the two functionally different human progesterone receptor forms A and B. EMBO J 1990; 9(5): 1603-14.
[PMID: 2328727]
, 10Chalbos D, Galtier F. Differential effect of forms A and B of human progesterone receptor on estradiol-dependent transcription. J Biol Chem 1994; 269(37): 23007-12.
[PMID: 8083200]
, 12Saint-Dizier M, Sandra O, Ployart S, Chebrout M, Constant F. Expression of nuclear progesterone receptor and progesterone receptor membrane components 1 and 2 in the oviduct of cyclic and pregnant cows during the post-ovulation period. Reprod Biol Endocrinol 2012; 10: 76.
[http://dx.doi.org/10.1186/1477-7827-10-76] [PMID: 22958265]
]. The primary structure of the nPR receptor is composed of domains with different conservativeness. The N-end is necessary for full transcriptional activity and is responsible for various, promoter-dependent properties of cell-specific nPR isoforms. Among functional domains, the DNA-binding domain (DBD; C region), less conservative ligand-binding domain (LBD; E region), and domains constitutively activating transcription (A/B region), can be distinguished [9Kastner P, Krust A, Turcotte B, et al. Two distinct estrogen-regulated promoters generate transcripts encoding the two functionally different human progesterone receptor forms A and B. EMBO J 1990; 9(5): 1603-14.
[PMID: 2328727]
, 10Chalbos D, Galtier F. Differential effect of forms A and B of human progesterone receptor on estradiol-dependent transcription. J Biol Chem 1994; 269(37): 23007-12.
[PMID: 8083200]
]. There are also two autonomous domains which activate transcription in the receptor structure: constitutive-activation domain AF-1 on the N-end, and AF-2 that is highly-conserved, ligand-dependent and localized on the C-end [13Chwalisz K, Perez MC, Demanno D, Winkel C, Schubert G, Elger W. Selective progesterone receptor modulator development and use in the treatment of leiomyomata and endometriosis. Endocr Rev 2005; 26(3): 423-38.
[http://dx.doi.org/10.1210/er.2005-0001] [PMID: 15857972]
]. The AF-1 structure is not conserved and little is known about its coactivators. The activity of AF-2 depends on transcriptional factor belonging to the family of p160 proteins. Additionally, nPRB contains an AF-3 domain in its chain (which is absent in nPRA) and probably inhibits, both its ID (inhibitory domain) and transcriptional activity [9Kastner P, Krust A, Turcotte B, et al. Two distinct estrogen-regulated promoters generate transcripts encoding the two functionally different human progesterone receptor forms A and B. EMBO J 1990; 9(5): 1603-14.
[PMID: 2328727]
, 14Edwards DP, Wardell SE, Boonyaratanakornkit V. Progesterone receptor interacting coregulatory proteins and cross talk with cell signaling pathways. J Steroid Biochem Mol Biol 2002; 83(1-5): 173-86.
[http://dx.doi.org/10.1016/S0960-0760(02)00265-0] [PMID: 12650714]
]. Also, nPR contains a short, proline-rich motif (amino acids 421-428), which mediates an interaction between the cytoplasmic domain of the receptor and the SH3 membrane domain (Src Homology 3 – domain of SRC tyrosine kinase) after binding with P4 [15Gellersen B, Fernandes MS, Brosens JJ. Non-genomic progesterone actions in female reproduction. Hum Reprod Update 2009; 15(1): 119-38.
[http://dx.doi.org/10.1093/humupd/dmn044] [PMID: 18936037]
].

The aspects of posttranslational modifications in ligand-dependent or ligand–independent manner, are crucial for nPR stability, localization and acivity [16Xin QL, Qiu JT, Cui S, Xia GL, Wang HB. Transcriptional activation of nuclear estrogen receptor and progesterone receptor and its regulation. Sheng Li Xue Bao 2016; 68(4): 435-54.
[PMID: 27546504]
]. They affect also glucocorticoid receptor (GR) complex formation and interaction with other agents or recruitment of cofactors [16Xin QL, Qiu JT, Cui S, Xia GL, Wang HB. Transcriptional activation of nuclear estrogen receptor and progesterone receptor and its regulation. Sheng Li Xue Bao 2016; 68(4): 435-54.
[PMID: 27546504]
, 17Leehy KA, Regan Anderson TM, Daniel AR, Lange CA, Ostrander JH. Modifications to glucocorticoid and progesterone receptors alter cell fate in breast cancer. J Mol Endocrinol 2016; 56(3): R99-R114.
[http://dx.doi.org/10.1530/JME-15-0322] [PMID: 26831511]
]. These modifications could be tissue-specific [18Das N, Jana CK. Tissue-specific effect of coenzyme Q10 supplementation on the oxidative post-translational modifications in the rat. Open Pharm Sci J 2016; 3: 196-202.] and involve phosphorylation, ubiquitination, methylation and so called SUMOylation (addition of small ubiquitin-related modifier – SUMO-peptides). What resembles the process of ubiquitination is a similarity of SUMO proteins to ubiquitin. The difference is that unlike ubiquitination, the process of posttranslational SUMOylation does not result in a degradation of target cells. It rather influences protein stabilization, localization, nuclear translocation, and particularly transcriptional activity. PR SUMOylation significantly suppresses transcriptional activity and vice versa, lack of SUMOylation induces PR transformation, especially nPRA, into a strong transcriptional activator [16Xin QL, Qiu JT, Cui S, Xia GL, Wang HB. Transcriptional activation of nuclear estrogen receptor and progesterone receptor and its regulation. Sheng Li Xue Bao 2016; 68(4): 435-54.
[PMID: 27546504]
]. Addition of SUMO peptides to lysine residues decreases GR transcriptional activity by corepressors recruitment, e.g. DAXX protein (death-domain associated protein). Furthermore, it cannot be excluded that SUMOylation induces a genome-wide chromatin occupancy redistribution of GR [17Leehy KA, Regan Anderson TM, Daniel AR, Lange CA, Ostrander JH. Modifications to glucocorticoid and progesterone receptors alter cell fate in breast cancer. J Mol Endocrinol 2016; 56(3): R99-R114.
[http://dx.doi.org/10.1530/JME-15-0322] [PMID: 26831511]
].

It seems that nPRA is vital for feminine reproductive functions and fertility, while nPRB determines proper development of the mammary gland in response to P4 [17Leehy KA, Regan Anderson TM, Daniel AR, Lange CA, Ostrander JH. Modifications to glucocorticoid and progesterone receptors alter cell fate in breast cancer. J Mol Endocrinol 2016; 56(3): R99-R114.
[http://dx.doi.org/10.1530/JME-15-0322] [PMID: 26831511]
, 19Conneely OM, Mulac-Jericevic B, Lydon JP. Progesterone-dependent regulation of female reproductive activity by two distinct progesterone receptor isoforms. Steroids 2003; 68(10-13): 771-8.
[http://dx.doi.org/10.1016/S0039-128X(03)00126-0] [PMID: 14667967]
, 20Mani SK, Reyna AM, Chen JZ, Mulac-Jericevic B, Conneely OM. Differential response of progesterone receptor isoforms in hormone-dependent and -independent facilitation of female sexual receptivity. Mol Endocrinol 2006; 20(6): 1322-32.
[http://dx.doi.org/10.1210/me.2005-0466] [PMID: 16484336]
]. It has been stated that female mice revealed a number of disorders, e.g. different sexual behavior, improper gonadotropin secretion, anovulatory cycles, deregulated uterine function, and invalid proliferation of the ductal or acinar cells in mammary glands after silencing genes for both nPR isoforms. The nPR receptor is also essential for the regulation of thymus involution during pregnancy and for augmented, P4-dependent, regulation of endothelial and smooth muscle cells proliferation in response to vessel detriment in the cardiovascular system [21Conneely OM, Mulac-Jericevic B, DeMayo F, Lydon JP, OMalley BW. Reproductive functions of progesterone receptors. Recent Prog Horm Res 2002; 57: 339-55.
[http://dx.doi.org/10.1210/rp.57.1.339] [PMID: 12017551]
].

The proportion of subtypes B/A of the nPR receptor varies in P4 target tissues and reveals interspecies differences. In chick oviduct, the number of both subtypes is more or less equal. In the human and mice myometrium nPRA is predominant, while in rabbit uterus the B isoform is the only one which is expressed [22Wang H, Critchley HO, Kelly RW, Shen D, Baird DT. Progesterone receptor subtype B is differentially regulated in human endometrial stroma. Mol Hum Reprod 1998; 4(4): 407-12.
[http://dx.doi.org/10.1093/molehr/4.4.407] [PMID: 9620842]
]. In humans, the level of expression of both isoforms is different in the course of the menstrual cycle and in various types of cells. In the endometrium, their expression undergoes specific fluctuations: it increases during the follicular phase and decreases after the ovulation [22Wang H, Critchley HO, Kelly RW, Shen D, Baird DT. Progesterone receptor subtype B is differentially regulated in human endometrial stroma. Mol Hum Reprod 1998; 4(4): 407-12.
[http://dx.doi.org/10.1093/molehr/4.4.407] [PMID: 9620842]
, 23Garcia E, Bouchard P, De Brux J, et al. Use of immunocytochemistry of progesterone and estrogen receptors for endometrial dating. J Clin Endocrinol Metab 1988; 67(1): 80-7.
[http://dx.doi.org/10.1210/jcem-67-1-80] [PMID: 2454244]
]. Estrogens induce mRNA and protein expression of both nPRs, especially of nPRB in chick oviduct, rat uterus and human endometrial cells. This activity increases the B/A ratio in favor of isoform B. In turn, nPR isoforms are down-regulated in the presence of their specific ligand – P4 [22Wang H, Critchley HO, Kelly RW, Shen D, Baird DT. Progesterone receptor subtype B is differentially regulated in human endometrial stroma. Mol Hum Reprod 1998; 4(4): 407-12.
[http://dx.doi.org/10.1093/molehr/4.4.407] [PMID: 9620842]
, 23Garcia E, Bouchard P, De Brux J, et al. Use of immunocytochemistry of progesterone and estrogen receptors for endometrial dating. J Clin Endocrinol Metab 1988; 67(1): 80-7.
[http://dx.doi.org/10.1210/jcem-67-1-80] [PMID: 2454244]
]. Diverse distribution of nPR isoforms in humans could implicate crucial clinical consequences. The nPRB/nPRA ratio determines the response of the tissue to P4 agonists or antagonists [22Wang H, Critchley HO, Kelly RW, Shen D, Baird DT. Progesterone receptor subtype B is differentially regulated in human endometrial stroma. Mol Hum Reprod 1998; 4(4): 407-12.
[http://dx.doi.org/10.1093/molehr/4.4.407] [PMID: 9620842]
]. Disturbed isoform balance or overexpression of one of them could contribute to the development of carcinomas in mammary glands, ovary and endometrium, or correlate with tumor progression into more aggressive forms [24Khan JA, Bellance C, Guiochon-Mantel A, Lombès M, Loosfelt H. Differential regulation of breast cancer-associated genes by progesterone receptor isoforms PRA and PRB in a new bi-inducible breast cancer cell line. PLoS One 2012; 7(9): e45993.
[http://dx.doi.org/10.1371/journal.pone.0045993] [PMID: 23029355]
].

Inactive nPR is associated with chaperone proteins (HSP) in the cytoplasm [25Rekawiecki R, Kowalik MK, Kotwica J. Nuclear progesterone receptor isoforms and their functions in the female reproductive tract. Pol J Vet Sci 2011; 14(1): 149-58.
[http://dx.doi.org/10.2478/v10181-011-0024-9] [PMID: 21528728]
]. Steroid hormones enter the interior of the cell both, passively by transmembrane diffusion or with participation of transporters [4Losel RM, Falkenstein E, Feuring M, et al. Nongenomic steroid action: controversies, questions, and answers. Physiol Rev 2003; 83(3): 965-1016.
[http://dx.doi.org/10.1152/physrev.00003.2003] [PMID: 12843413]
]. Subsequently, they bind to intracellular receptors. Then, the receptors undergo conformational changes, chaperon proteins dissociate and the DNA-binding domain gains higher affinity [4Losel RM, Falkenstein E, Feuring M, et al. Nongenomic steroid action: controversies, questions, and answers. Physiol Rev 2003; 83(3): 965-1016.
[http://dx.doi.org/10.1152/physrev.00003.2003] [PMID: 12843413]
, 25Rekawiecki R, Kowalik MK, Kotwica J. Nuclear progesterone receptor isoforms and their functions in the female reproductive tract. Pol J Vet Sci 2011; 14(1): 149-58.
[http://dx.doi.org/10.2478/v10181-011-0024-9] [PMID: 21528728]
]. The steroid-receptor complex migrates to the nucleus and the DNA-binding domain is exposed. In the cell nucleus, the receptor dimerizes and joins its matching coactivators: SRC and CBP (CREBP Binding Protein), and then interacts with HRE. The final effect of signal transduction is the initiation of transcription and subsequently translation [9Kastner P, Krust A, Turcotte B, et al. Two distinct estrogen-regulated promoters generate transcripts encoding the two functionally different human progesterone receptor forms A and B. EMBO J 1990; 9(5): 1603-14.
[PMID: 2328727]
, 25Rekawiecki R, Kowalik MK, Kotwica J. Nuclear progesterone receptor isoforms and their functions in the female reproductive tract. Pol J Vet Sci 2011; 14(1): 149-58.
[http://dx.doi.org/10.2478/v10181-011-0024-9] [PMID: 21528728]
]. This process involves the cell genome and it has been described as the classical, genomic pathway. The completion of this process requires a significantly prolonged period of time in comparison to shorter non-classical, extragenomic pathways. The genomic pathway is sensitive to transcription or translation inhibitors, like actinomycin D and cycloheximide, respectively [4Losel RM, Falkenstein E, Feuring M, et al. Nongenomic steroid action: controversies, questions, and answers. Physiol Rev 2003; 83(3): 965-1016.
[http://dx.doi.org/10.1152/physrev.00003.2003] [PMID: 12843413]
].

3. NON-CLASSICAL PATHWAY

A number of steroid effects cannot be simply explained by functioning of the classical, genomic mechanism. Steroids were discovered to initiate rapid intracellular processes, unusual for nuclear signaling [26Thomas P. Characteristics of membrane progestin receptor alpha (mPRalpha) and progesterone membrane receptor component 1 (PGMRC1) and their roles in mediating rapid progestin actions. Front Neuroendocrinol 2008; 29(2): 292-312.
[http://dx.doi.org/10.1016/j.yfrne.2008.01.001] [PMID: 18343488]
, 27Adlanmerini M, Solinhac R, Abot A, et al. Mutation of the palmitoylation site of estrogen receptor α in vivo reveals tissue-specific roles for membrane versus nuclear actions. Proc Natl Acad Sci USA 2014; 111(2): E283-90.
[http://dx.doi.org/10.1073/pnas.1322057111] [PMID: 24371309]
]. They result in changes of ion channel conductivity, concentration of intracellular calcium, and second messengers (like cyclic nucleotides), as well as modifications in the activity of Erk 1 and 2 kinases [26Thomas P. Characteristics of membrane progestin receptor alpha (mPRalpha) and progesterone membrane receptor component 1 (PGMRC1) and their roles in mediating rapid progestin actions. Front Neuroendocrinol 2008; 29(2): 292-312.
[http://dx.doi.org/10.1016/j.yfrne.2008.01.001] [PMID: 18343488]
, 27Adlanmerini M, Solinhac R, Abot A, et al. Mutation of the palmitoylation site of estrogen receptor α in vivo reveals tissue-specific roles for membrane versus nuclear actions. Proc Natl Acad Sci USA 2014; 111(2): E283-90.
[http://dx.doi.org/10.1073/pnas.1322057111] [PMID: 24371309]
]. The wide spectrum of cells and tissues, where rapid, non-genomic effects appear, supports the fact that it is rather a universal process, and not a rare phenomenon [4Losel RM, Falkenstein E, Feuring M, et al. Nongenomic steroid action: controversies, questions, and answers. Physiol Rev 2003; 83(3): 965-1016.
[http://dx.doi.org/10.1152/physrev.00003.2003] [PMID: 12843413]
]. The non-genomic signaling could be relevant for proper development and function of the tissues and organs [28Pedram A, Razandi M, Lewis M, Hammes S, Levin ER. Membrane-localized estrogen receptor α is required for normal organ development and function. Dev Cell 2014; 29(4): 482-90.
[http://dx.doi.org/10.1016/j.devcel.2014.04.016] [PMID: 24871949]
].

Three different mechanisms of non-genomic (non-classical) pathway have been suggested: (1) ‘the side-effect’ of the classical pathway (especially P4 and estrogens); (2) non-specific, direct effects at the level of cell membrane (principally in relation to glucocorticoids, because they are present at high concentrations), and (3) via non-classical receptors [4Losel RM, Falkenstein E, Feuring M, et al. Nongenomic steroid action: controversies, questions, and answers. Physiol Rev 2003; 83(3): 965-1016.
[http://dx.doi.org/10.1152/physrev.00003.2003] [PMID: 12843413]
]. Newly recognized receptor proteins not associated with previously described receptors, nuclear steroid receptors, receptors for other ligands exhibiting similarity to steroids, and GABAa and oxytocin receptors which have the ability to bind progestagens, have all been suggested as the components of this non-classical pathway [26Thomas P. Characteristics of membrane progestin receptor alpha (mPRalpha) and progesterone membrane receptor component 1 (PGMRC1) and their roles in mediating rapid progestin actions. Front Neuroendocrinol 2008; 29(2): 292-312.
[http://dx.doi.org/10.1016/j.yfrne.2008.01.001] [PMID: 18343488]
]. It seems that signaling initiated on the cell surface by binding hormones to specific membrane receptors is the most probable among these three mechanisms [29Zhu Y, Rice CD, Pang Y, Pace M, Thomas P. Cloning, expression, and characterization of a membrane progestin receptor and evidence it is an intermediary in meiotic maturation of fish oocytes. Proc Natl Acad Sci USA 2003; 100(5): 2231-6.
[http://dx.doi.org/10.1073/pnas.0336132100] [PMID: 12574519]
]. Nonetheless, some aspects of progestagen activity remain unexplained [26Thomas P. Characteristics of membrane progestin receptor alpha (mPRalpha) and progesterone membrane receptor component 1 (PGMRC1) and their roles in mediating rapid progestin actions. Front Neuroendocrinol 2008; 29(2): 292-312.
[http://dx.doi.org/10.1016/j.yfrne.2008.01.001] [PMID: 18343488]
]. The biological activity which is mediated by membrane receptors could be both, rapid like sperm motility, and slightly slower like oocyte maturation in fish or amphibians [26Thomas P. Characteristics of membrane progestin receptor alpha (mPRalpha) and progesterone membrane receptor component 1 (PGMRC1) and their roles in mediating rapid progestin actions. Front Neuroendocrinol 2008; 29(2): 292-312.
[http://dx.doi.org/10.1016/j.yfrne.2008.01.001] [PMID: 18343488]
, 30Friberg PA, Larsson DG, Billig H. Dominant role of nuclear progesterone receptor in the control of rat periovulatory granulosa cell apoptosis. Biol Reprod 2009; 80(6): 1160-7.
[http://dx.doi.org/10.1095/biolreprod.108.073932] [PMID: 19208546]
].

Non-classical, rapid signal transduction of P4 signaling is suggested in many cells and tissues: spermatozoa, oocytes, corpora lutea, Leydig cells, as well as in uterine myometrium, hepatocytes, brain, and neoplastic cells of breast carcinoma [26Thomas P. Characteristics of membrane progestin receptor alpha (mPRalpha) and progesterone membrane receptor component 1 (PGMRC1) and their roles in mediating rapid progestin actions. Front Neuroendocrinol 2008; 29(2): 292-312.
[http://dx.doi.org/10.1016/j.yfrne.2008.01.001] [PMID: 18343488]
, 31Hammes SR. The further redefining of steroid-mediated signaling. Proc Natl Acad Sci USA 2003; 100(5): 2168-70.
[http://dx.doi.org/10.1073/pnas.0530224100] [PMID: 12606724]
]. It has been demonstrated, that the acrosome reaction is induced with mediation of membrane receptors [32Tubbs C, Thomas P. Functional characteristics of membrane progestin receptor alpha (mPRalpha) subtypes: a review with new data showing mPRalpha expression in seatrout sperm and its association with sperm motility. Steroids 2008; 73(9-10): 935-41.
[http://dx.doi.org/10.1016/j.steroids.2007.12.022] [PMID: 18275978]
]. In some fishes (Genyonemus lineatus and Cynoscion regalis), decreased mPRα expression correlated with impaired sperm motility (asthenozoospermia) [26Thomas P. Characteristics of membrane progestin receptor alpha (mPRalpha) and progesterone membrane receptor component 1 (PGMRC1) and their roles in mediating rapid progestin actions. Front Neuroendocrinol 2008; 29(2): 292-312.
[http://dx.doi.org/10.1016/j.yfrne.2008.01.001] [PMID: 18343488]
]. More evidence has been delivered from studies concerning membrane receptors expression in female mice and rats. Mice with nPR gene knock-out demonstrated fertility perturbations. In rat ovaries, nPR has not been expressed in granulosa and corpora lutea cells, despite the fact that at the same time P4 demonstrated its suppressor activity regarding the apoptosis of granulosa cells and its autocrine activity in luteal cells [15Gellersen B, Fernandes MS, Brosens JJ. Non-genomic progesterone actions in female reproduction. Hum Reprod Update 2009; 15(1): 119-38.
[http://dx.doi.org/10.1093/humupd/dmn044] [PMID: 18936037]
, 33Chappell PE, Lydon JP, Conneely OM, OMalley BW, Levine JE. Endocrine defects in mice carrying a null mutation for the progesterone receptor gene. Endocrinology 1997; 138(10): 4147-52.
[PMID: 9322923]
].

Further evidence for rapid membrane signaling is the steroid hormone activity in the central nervous system (CNS), where the hormones dynamically induce neuronal excitability changes, neuroendocrine reactions and behavioral effects [34Majewska MD, Harrison NL, Schwartz RD, Barker JL, Paul SM. Steroid hormone metabolites are barbiturate-like modulators of the GABA receptor. Science 1986; 232(4753): 1004-7.
[http://dx.doi.org/10.1126/science.2422758] [PMID: 2422758]
]. Stimulation of the membrane receptor-dependent GnRH secretion in ventral tegmental area, affecting sexual receptivity in rodents, is among these reactions. In rats, this phenomenon appears 10 minutes after i.v. P4 infusion (20-400 µg). It seems to be independent of nPR presence in ventromedial hypothalamus as there is no evidence of nuclear receptor presence in this localization. Possibly, that activity could be implemented through GABAa/benzodiazepines receptor [4Losel RM, Falkenstein E, Feuring M, et al. Nongenomic steroid action: controversies, questions, and answers. Physiol Rev 2003; 83(3): 965-1016.
[http://dx.doi.org/10.1152/physrev.00003.2003] [PMID: 12843413]
, 26Thomas P. Characteristics of membrane progestin receptor alpha (mPRalpha) and progesterone membrane receptor component 1 (PGMRC1) and their roles in mediating rapid progestin actions. Front Neuroendocrinol 2008; 29(2): 292-312.
[http://dx.doi.org/10.1016/j.yfrne.2008.01.001] [PMID: 18343488]
, 34Majewska MD, Harrison NL, Schwartz RD, Barker JL, Paul SM. Steroid hormone metabolites are barbiturate-like modulators of the GABA receptor. Science 1986; 232(4753): 1004-7.
[http://dx.doi.org/10.1126/science.2422758] [PMID: 2422758]
, 35Zhu Y, Bond J, Thomas P. Identification, classification, and partial characterization of genes in humans and other vertebrates homologous to a fish membrane progestin receptor. Proc Natl Acad Sci USA 2003; 100(5): 2237-42.
[http://dx.doi.org/10.1073/pnas.0436133100] [PMID: 12601167]
]. Not merely P4 per se, but also its metabolites seem to participate in the extragenomic signal transduction. For instance, 5α-pregnan-3,20-dion and 3α-hydroksy-4-pregnan-20-one bind to membrane fractions of the neoplastic cells in breast carcinoma and porcine hepatocytes [4Losel RM, Falkenstein E, Feuring M, et al. Nongenomic steroid action: controversies, questions, and answers. Physiol Rev 2003; 83(3): 965-1016.
[http://dx.doi.org/10.1152/physrev.00003.2003] [PMID: 12843413]
]. Other P4 metabolites, like 3α-hydroksy-5α-dihydroprogesterone, or deoxycorticosterone metabolites, like 3α,5α-tetrahydrodeoxycorticosterone, could modulate the function of the GABA receptor and act in the same subcellular localization as barbiturates [4Losel RM, Falkenstein E, Feuring M, et al. Nongenomic steroid action: controversies, questions, and answers. Physiol Rev 2003; 83(3): 965-1016.
[http://dx.doi.org/10.1152/physrev.00003.2003] [PMID: 12843413]
, 34Majewska MD, Harrison NL, Schwartz RD, Barker JL, Paul SM. Steroid hormone metabolites are barbiturate-like modulators of the GABA receptor. Science 1986; 232(4753): 1004-7.
[http://dx.doi.org/10.1126/science.2422758] [PMID: 2422758]
].

Modulated function of the immunological system in humans constitutes an another aspect arising from the analysis of P4 activity spectrum. Some kind of diversity in the immunological response can be observed in pregnancy, in the luteal phase of the menstrual cycle, or in the course of some diseases, especially those related to autoaggression. The significance of membrane receptors in these issues is associated with the presence of membrane receptors: mPRα and mPRβ on the leukocytes of the peripheral blood and T lymphocytes in the reproductive age, as well as on immortalized cells of human T lymphocyte line (Jurkat cells), with simultaneous exclusion of nPR presence [26Thomas P. Characteristics of membrane progestin receptor alpha (mPRalpha) and progesterone membrane receptor component 1 (PGMRC1) and their roles in mediating rapid progestin actions. Front Neuroendocrinol 2008; 29(2): 292-312.
[http://dx.doi.org/10.1016/j.yfrne.2008.01.001] [PMID: 18343488]
, 36Dosiou C, Hamilton AE, Pang Y, et al. Expression of membrane progesterone receptors on human T lymphocytes and Jurkat cells and activation of G-proteins by progesterone. J Endocrinol 2008; 196(1): 67-77.
[http://dx.doi.org/10.1677/JOE-07-0317] [PMID: 18180318]
]. It has been proven that mPRα expression on CD8+ T lymphocytes increases approximately two-fold in the luteal phase of menstrual cycle, but not on CD4+, what promotes humoral immune response [26Thomas P. Characteristics of membrane progestin receptor alpha (mPRalpha) and progesterone membrane receptor component 1 (PGMRC1) and their roles in mediating rapid progestin actions. Front Neuroendocrinol 2008; 29(2): 292-312.
[http://dx.doi.org/10.1016/j.yfrne.2008.01.001] [PMID: 18343488]
].

It has been also demonstrated that PR, as estrogen receptors, is present on β cells of islets of Langerhans, and seems to regulate the functions and the survival of β cells [37Brănişteanu DD, Mathieu C. Progesterone in gestational diabetes mellitus: guilty or not guilty? Trends Endocrinol Metab 2003; 14(2): 54-6.
[http://dx.doi.org/10.1016/S1043-2760(03)00003-1] [PMID: 12591170]
, 38Nadal A, Alonso-Magdalena P, Soriano S, Ropero AB, Quesada I. The role of oestrogens in the adaptation of islets to insulin resistance. J Physiol 2009; 587(Pt 21): 5031-7.
[http://dx.doi.org/10.1113/jphysiol.2009.177188] [PMID: 19687125]
]. P4 has been suggested to be the key hormone in the development of gestational diabetes, since it is known to be relevant for insulin secretion and pancreatic function [39Picard F, Wanatabe M, Schoonjans K, Lydon J, OMalley BW, Auwerx J. Progesterone receptor knockout mice have an improved glucose homeostasis secondary to beta -cell proliferation. Proc Natl Acad Sci USA 2002; 99(24): 15644-8.
[http://dx.doi.org/10.1073/pnas.202612199] [PMID: 12438645]
]. The mechanism of P4 activity probably involves a decrease of GLUT4 expression and an impairment of glucose uptake by the skeletal muscles. Simultaneously, PR antagonist – RU486, decreases glucose serum concentration [30Friberg PA, Larsson DG, Billig H. Dominant role of nuclear progesterone receptor in the control of rat periovulatory granulosa cell apoptosis. Biol Reprod 2009; 80(6): 1160-7.
[http://dx.doi.org/10.1095/biolreprod.108.073932] [PMID: 19208546]
]. It should also be noted that P4 exhibits a suppressive influence on pancreatic cell proliferation, and the stage of malignancy of tumors derived from the endocrine part of pancreas negatively correlates with PR immunoreactivity.

In P4 signalization the family of membrane heptahelical receptors coupled with G-proteins probably play the key role [6Pedram A, Razandi M, Sainson RC, Kim JK, Hughes CC, Levin ER. A conserved mechanism for steroid receptor translocation to the plasma membrane. J Biol Chem 2007; 282(31): 22278-88.
[http://dx.doi.org/10.1074/jbc.M611877200] [PMID: 17535799]
]. Activation of G proteins results in cyclic nucleotide production, calcium transport, and rapid activation of kinase cascade [40Razandi M, Pedram A, Levin ER. Heat shock protein 27 is required for sex steroid receptor trafficking to and functioning at the plasma membrane. Mol Cell Biol 2010; 30(13): 3249-61.
[http://dx.doi.org/10.1128/MCB.01354-09] [PMID: 20439495]
]. Every impairment regarding this pathway could implicate disturbances on molecular level, like trouble in cell signaling, i.e. in MAPK and PI3 activation. Some factors, like point mutations of membrane receptor genes, can lead to the loss of phenylalanine, cysteine or tyrosine from the polypeptide chain, and impair proper receptor localization in cell membrane. Disturbances in proper cell signaling translate into clinical features. For instance, it seems that the development of aggressive forms of breast carcinoma or resistance to tamoxifen could stem from lack of palmitoylation or prolonged receptor existence in caveolae [40Razandi M, Pedram A, Levin ER. Heat shock protein 27 is required for sex steroid receptor trafficking to and functioning at the plasma membrane. Mol Cell Biol 2010; 30(13): 3249-61.
[http://dx.doi.org/10.1128/MCB.01354-09] [PMID: 20439495]
].

3.1. PAQR Family and mPR Receptor

The PAQR (Progesterone Adiponectin Q Receptor) family comprises highly conserved proteins with high amino acid homology, occurring in many organisms, from Eubacteria to Eutheria [15Gellersen B, Fernandes MS, Brosens JJ. Non-genomic progesterone actions in female reproduction. Hum Reprod Update 2009; 15(1): 119-38.
[http://dx.doi.org/10.1093/humupd/dmn044] [PMID: 18936037]
, 41Krietsch T, Fernandes MS, Kero J, et al. Human homologs of the putative G protein-coupled membrane progestin receptors (mPRalpha, beta, and gamma) localize to the endoplasmic reticulum and are not activated by progesterone. Mol Endocrinol 2006; 20(12): 3146-64.
[http://dx.doi.org/10.1210/me.2006-0129] [PMID: 16959873]
]. Its members are identified in Arabidopsis, Drosophila, Caenorhabditis elegans, Xenopus, Danio rerio, Fugu, and birds [35Zhu Y, Bond J, Thomas P. Identification, classification, and partial characterization of genes in humans and other vertebrates homologous to a fish membrane progestin receptor. Proc Natl Acad Sci USA 2003; 100(5): 2237-42.
[http://dx.doi.org/10.1073/pnas.0436133100] [PMID: 12601167]
, 42Fernandes MS, Pierron V, Michalovich D, et al. Regulated expression of putative membrane progestin receptor homologues in human endometrium and gestational tissues. J Endocrinol 2005; 187(1): 89-101.
[http://dx.doi.org/10.1677/joe.1.06242] [PMID: 16214944]
]. mPRs have their receptor equivalents in the PAQR family. mPR is an oligomeric protein complex with the molecular mass of about 40 kDa. It includes three mPR subtypes: α, β and γ. The proofs that PAQR family members are bona fide P4 receptors come from the studies on knockout animals with inoperative selected PAQR receptors. For example, in PRKO mice, a decrease in LH secretion by P4 was mediated by a membrane progesterone receptor [26Thomas P. Characteristics of membrane progestin receptor alpha (mPRalpha) and progesterone membrane receptor component 1 (PGMRC1) and their roles in mediating rapid progestin actions. Front Neuroendocrinol 2008; 29(2): 292-312.
[http://dx.doi.org/10.1016/j.yfrne.2008.01.001] [PMID: 18343488]
, 43Pru JK, Clark NC. PGRMC1 and PGRMC2 in uterine physiology and disease. Front Neurosci 2013; 7: 168.
[http://dx.doi.org/10.3389/fnins.2013.00168] [PMID: 24065879]
].

The core region containing seven transmembrane domains and four highly conserved metal-binding motifs is the common and dominant feature of proteins belonging to the PAQR family [42Fernandes MS, Pierron V, Michalovich D, et al. Regulated expression of putative membrane progestin receptor homologues in human endometrium and gestational tissues. J Endocrinol 2005; 187(1): 89-101.
[http://dx.doi.org/10.1677/joe.1.06242] [PMID: 16214944]
]. Three subfamilies have been distinguished within the PAQR family on the basis of phylogenetic analysis: receptors related to adiponectin, membrane receptors for progestins, and receptors associated with hemolysin III. Generally, 11 proteins typical for mammals (PAQR I-XI), as well as hemolysin III derived from Bacillus cereus (HLYIII), YOLOOLC and Sacharomyces cerevisiae proteins have been included [42Fernandes MS, Pierron V, Michalovich D, et al. Regulated expression of putative membrane progestin receptor homologues in human endometrium and gestational tissues. J Endocrinol 2005; 187(1): 89-101.
[http://dx.doi.org/10.1677/joe.1.06242] [PMID: 16214944]
, 44Kazeto Y, Goto-Kazeto R, Thomas P, Trant JM. Molecular characterization of three forms of putative membrane-bound progestin receptors and their tissue-distribution in channel catfish, Ictalurus punctatus. J Mol Endocrinol 2005; 34(3): 781-91.
[http://dx.doi.org/10.1677/jme.1.01721] [PMID: 15956347]
]. Adiponectin receptors: PAQR I, II, III, IV, YOLOO2C and other yeast proteins, transmembrane adiponectin receptors 1 and 2 (adipoRs) derived from Eubacteria, are all involved in lipid homeostasis regulation (especially fatty acids), as well as phosphate and zinc metabolism. PAQR I and II are involved in adipokine (adiponectin) binding [15Gellersen B, Fernandes MS, Brosens JJ. Non-genomic progesterone actions in female reproduction. Hum Reprod Update 2009; 15(1): 119-38.
[http://dx.doi.org/10.1093/humupd/dmn044] [PMID: 18936037]
, 42Fernandes MS, Pierron V, Michalovich D, et al. Regulated expression of putative membrane progestin receptor homologues in human endometrium and gestational tissues. J Endocrinol 2005; 187(1): 89-101.
[http://dx.doi.org/10.1677/joe.1.06242] [PMID: 16214944]
].

Human gene for mPRα consists of three exons separated by two introns, gene for mPRβ has two exons and one additional intron in comparison to mPRα, while the gene for mPRγ is composed of eight exons and seven introns [5Bramley T. Non-genomic progesterone receptors in the mammalian ovary: some unresolved issues. Reproduction 2003; 125(1): 3-15.
[http://dx.doi.org/10.1530/rep.0.1250003] [PMID: 12622691]
, 44Kazeto Y, Goto-Kazeto R, Thomas P, Trant JM. Molecular characterization of three forms of putative membrane-bound progestin receptors and their tissue-distribution in channel catfish, Ictalurus punctatus. J Mol Endocrinol 2005; 34(3): 781-91.
[http://dx.doi.org/10.1677/jme.1.01721] [PMID: 15956347]
]. 5’-end is deprived of typical TATA sequence (TATA box); the proximal region is abundant in GC pairs. Some motifs regulating DNA synthesis, like AP2, NF-AT, CIEBP and AhR/Arnt, have been identified [5Bramley T. Non-genomic progesterone receptors in the mammalian ovary: some unresolved issues. Reproduction 2003; 125(1): 3-15.
[http://dx.doi.org/10.1530/rep.0.1250003] [PMID: 12622691]
]. The transcripts for human mPR isoforms differ in molecular mass within the range of 2.8 to 5.8 kb [35Zhu Y, Bond J, Thomas P. Identification, classification, and partial characterization of genes in humans and other vertebrates homologous to a fish membrane progestin receptor. Proc Natl Acad Sci USA 2003; 100(5): 2237-42.
[http://dx.doi.org/10.1073/pnas.0436133100] [PMID: 12601167]
]. In catfish, amino acid homology among mPR subtypes, i.e. between α and β, is 50%, whereas among γ and the remaining two is less than 30% [44Kazeto Y, Goto-Kazeto R, Thomas P, Trant JM. Molecular characterization of three forms of putative membrane-bound progestin receptors and their tissue-distribution in channel catfish, Ictalurus punctatus. J Mol Endocrinol 2005; 34(3): 781-91.
[http://dx.doi.org/10.1677/jme.1.01721] [PMID: 15956347]
].

In general, both recombinant and wild receptor types display high affinity and specificity of P4 binding [26Thomas P. Characteristics of membrane progestin receptor alpha (mPRalpha) and progesterone membrane receptor component 1 (PGMRC1) and their roles in mediating rapid progestin actions. Front Neuroendocrinol 2008; 29(2): 292-312.
[http://dx.doi.org/10.1016/j.yfrne.2008.01.001] [PMID: 18343488]
]. It is possible to distinguish extracellular N-end and intracellular C-end in their structure [35Zhu Y, Bond J, Thomas P. Identification, classification, and partial characterization of genes in humans and other vertebrates homologous to a fish membrane progestin receptor. Proc Natl Acad Sci USA 2003; 100(5): 2237-42.
[http://dx.doi.org/10.1073/pnas.0436133100] [PMID: 12601167]
]. mPR, especially mPRα, is directly coupled with G-proteins and typically activates pertussis toxin-sensitive inhibitory Gi protein, ultimately leading to adenylate cyclase down-regulation and decrease in cAMP concentration [26Thomas P. Characteristics of membrane progestin receptor alpha (mPRalpha) and progesterone membrane receptor component 1 (PGMRC1) and their roles in mediating rapid progestin actions. Front Neuroendocrinol 2008; 29(2): 292-312.
[http://dx.doi.org/10.1016/j.yfrne.2008.01.001] [PMID: 18343488]
]. However, the analysis of the mPRβ signal path revealed that the receptor is not sensitive to pertussis and cholera toxins, what suggests that it activates another G-protein, insusceptible to the aforementioned toxins [45Thomas P, Pang Y, Dong J, et al. Steroid and G protein binding characteristics of the seatrout and human progestin membrane receptor alpha subtypes and their evolutionary origins. Endocrinology 2007; 148(2): 705-18.
[http://dx.doi.org/10.1210/en.2006-0974] [PMID: 17082257]
, 46Hanna R, Pang Y, Thomas P, Zhu Y. Cell-surface expression, progestin binding, and rapid nongenomic signaling of zebrafish membrane progestin receptors alpha and beta in transfected cells. J Endocrinol 2006; 190(2): 247-60.
[http://dx.doi.org/10.1677/joe.1.06694] [PMID: 16899559]
].

mRNA for mPRs is widely distributed in both, reproductive and non-reproductive tissues of vertebrates, what indicates multipotent properties of membrane receptors [26Thomas P. Characteristics of membrane progestin receptor alpha (mPRalpha) and progesterone membrane receptor component 1 (PGMRC1) and their roles in mediating rapid progestin actions. Front Neuroendocrinol 2008; 29(2): 292-312.
[http://dx.doi.org/10.1016/j.yfrne.2008.01.001] [PMID: 18343488]
]. Transcripts of mPRα have been identified in the ovaries (corpus luteum), testes, placenta, amnion, chorion, uterus (myometrium and endometrium), mammary gland, brain (hypothalamus, hypophysis), heart, intestines, liver, spleen, skeletal muscles, adrenal glands, and lungs [26Thomas P. Characteristics of membrane progestin receptor alpha (mPRalpha) and progesterone membrane receptor component 1 (PGMRC1) and their roles in mediating rapid progestin actions. Front Neuroendocrinol 2008; 29(2): 292-312.
[http://dx.doi.org/10.1016/j.yfrne.2008.01.001] [PMID: 18343488]
, 35Zhu Y, Bond J, Thomas P. Identification, classification, and partial characterization of genes in humans and other vertebrates homologous to a fish membrane progestin receptor. Proc Natl Acad Sci USA 2003; 100(5): 2237-42.
[http://dx.doi.org/10.1073/pnas.0436133100] [PMID: 12601167]
]. Transcripts of mPRβ have been identified in the brain, hypophysis, ovaries and testes, and mPRγ - in the abdominal aorta, and intestines [31Hammes SR. The further redefining of steroid-mediated signaling. Proc Natl Acad Sci USA 2003; 100(5): 2168-70.
[http://dx.doi.org/10.1073/pnas.0530224100] [PMID: 12606724]
, 35Zhu Y, Bond J, Thomas P. Identification, classification, and partial characterization of genes in humans and other vertebrates homologous to a fish membrane progestin receptor. Proc Natl Acad Sci USA 2003; 100(5): 2237-42.
[http://dx.doi.org/10.1073/pnas.0436133100] [PMID: 12601167]
, 44Kazeto Y, Goto-Kazeto R, Thomas P, Trant JM. Molecular characterization of three forms of putative membrane-bound progestin receptors and their tissue-distribution in channel catfish, Ictalurus punctatus. J Mol Endocrinol 2005; 34(3): 781-91.
[http://dx.doi.org/10.1677/jme.1.01721] [PMID: 15956347]
]. A significant level of the expression of all three subtypes has been demonstrated only in kidneys [35Zhu Y, Bond J, Thomas P. Identification, classification, and partial characterization of genes in humans and other vertebrates homologous to a fish membrane progestin receptor. Proc Natl Acad Sci USA 2003; 100(5): 2237-42.
[http://dx.doi.org/10.1073/pnas.0436133100] [PMID: 12601167]
]. Therefore, mPRs expression seems to be tissue-specific. Subunit α dominates in reproductive tissues, β in nervous tissue, and γ in the alimentary tract [42Fernandes MS, Pierron V, Michalovich D, et al. Regulated expression of putative membrane progestin receptor homologues in human endometrium and gestational tissues. J Endocrinol 2005; 187(1): 89-101.
[http://dx.doi.org/10.1677/joe.1.06242] [PMID: 16214944]
]. This is in contrast with the fact of tissue specificity of nuclear receptors, which tend to appear primarily in brain and gonads, and have potential abilities to form heterodimers, what is almost impossible in case of mPR in most human tissues [35Zhu Y, Bond J, Thomas P. Identification, classification, and partial characterization of genes in humans and other vertebrates homologous to a fish membrane progestin receptor. Proc Natl Acad Sci USA 2003; 100(5): 2237-42.
[http://dx.doi.org/10.1073/pnas.0436133100] [PMID: 12601167]
]. Currently, the significance of such diverse distribution of three mPR subtypes is not clear. One of the possible explanations for different mRNA mPRβ localization in the nervous tissue is the fact that mPRβ is a subtype typical for tissues derived from ectoderm. On the other hand, mPRβ was obtained from mouse testes, which originate from the mesoderm. In turn, in Cynoscion regalis, subtype α has been found in the brain, what suggests that both, subtype β and α could be mediators of P4 activity initiated on the neuron surface in vertebrate brain. Thus, subtype α mediates not only rapid, non-genomic P4 action in reproductive tissues [35Zhu Y, Bond J, Thomas P. Identification, classification, and partial characterization of genes in humans and other vertebrates homologous to a fish membrane progestin receptor. Proc Natl Acad Sci USA 2003; 100(5): 2237-42.
[http://dx.doi.org/10.1073/pnas.0436133100] [PMID: 12601167]
].

mPR isoforms differ among species in tissue distribution and the level of expression during the menstrual cycle, thus implying their diverse physiologic functions [26Thomas P. Characteristics of membrane progestin receptor alpha (mPRalpha) and progesterone membrane receptor component 1 (PGMRC1) and their roles in mediating rapid progestin actions. Front Neuroendocrinol 2008; 29(2): 292-312.
[http://dx.doi.org/10.1016/j.yfrne.2008.01.001] [PMID: 18343488]
, 47Peluso JJ. Multiplicity of progesterones actions and receptors in the mammalian ovary. Biol Reprod 2006; 75(1): 2-8.
[http://dx.doi.org/10.1095/biolreprod.105.049924] [PMID: 16452458]
]. mPRα, γ and PAQR IX expression in the endometrium depends on the phase of the ovarian cycle, and initiation of parturition is associated with significant reduction of mPR α and β concentration in the myometrium. mPRα and PAQR IX are significantly expressed in the placenta [42Fernandes MS, Pierron V, Michalovich D, et al. Regulated expression of putative membrane progestin receptor homologues in human endometrium and gestational tissues. J Endocrinol 2005; 187(1): 89-101.
[http://dx.doi.org/10.1677/joe.1.06242] [PMID: 16214944]
]. What is relevant, changes in mPRs distribution constitute not only morphological but also functional diversity. Therefore, modulation of mPRα expression has been demonstrated in both, physiologic (e.g. during the ovarian cycle), and pathologic processes (malignant proliferative processes, e.g. in human mammary gland). It underlines the relevant physiologic role of the receptor in a wide range of organs and tissues, and also during carcinogenesis [26Thomas P. Characteristics of membrane progestin receptor alpha (mPRalpha) and progesterone membrane receptor component 1 (PGMRC1) and their roles in mediating rapid progestin actions. Front Neuroendocrinol 2008; 29(2): 292-312.
[http://dx.doi.org/10.1016/j.yfrne.2008.01.001] [PMID: 18343488]
].

3.2. PGRMC1 Receptor

PGRMC1 (Progesterone Receptor Membrane Component One) is the membrane protein with the molecular mass of approximately 26-28 kDa. It has been primarily isolated from porcine liver microsomes, and then identified in other tissues, like smooth muscle cells [12Saint-Dizier M, Sandra O, Ployart S, Chebrout M, Constant F. Expression of nuclear progesterone receptor and progesterone receptor membrane components 1 and 2 in the oviduct of cyclic and pregnant cows during the post-ovulation period. Reprod Biol Endocrinol 2012; 10: 76.
[http://dx.doi.org/10.1186/1477-7827-10-76] [PMID: 22958265]
, 26Thomas P. Characteristics of membrane progestin receptor alpha (mPRalpha) and progesterone membrane receptor component 1 (PGMRC1) and their roles in mediating rapid progestin actions. Front Neuroendocrinol 2008; 29(2): 292-312.
[http://dx.doi.org/10.1016/j.yfrne.2008.01.001] [PMID: 18343488]
, 41Krietsch T, Fernandes MS, Kero J, et al. Human homologs of the putative G protein-coupled membrane progestin receptors (mPRalpha, beta, and gamma) localize to the endoplasmic reticulum and are not activated by progesterone. Mol Endocrinol 2006; 20(12): 3146-64.
[http://dx.doi.org/10.1210/me.2006-0129] [PMID: 16959873]
, 48Falkenstein E, Meyer C, Eisen C, Scriba PC, Wehling M. Full-length cDNA sequence of a progesterone membrane-binding protein from porcine vascular smooth muscle cells. Biochem Biophys Res Commun 1996; 229(1): 86-9.
[http://dx.doi.org/10.1006/bbrc.1996.1761] [PMID: 8954087]
-50Krebs CJ, Jarvis ED, Chan J, Lydon JP, Ogawa S, Pfaff DW. A membrane-associated progesterone-binding protein, 25-Dx, is regulated by progesterone in brain regions involved in female reproductive behaviors. Proc Natl Acad Sci USA 2000; 97(23): 12816-21.
[http://dx.doi.org/10.1073/pnas.97.23.12816] [PMID: 11070092]
]. In humans, the receptor was identified in 1996 and is known as Hpr6.6 (Human P4 receptor). In rats, it is called RDA 288, with the mass of about 60 kDa, and it has been obtained from hepatocytes and granulosa cells [26Thomas P. Characteristics of membrane progestin receptor alpha (mPRalpha) and progesterone membrane receptor component 1 (PGMRC1) and their roles in mediating rapid progestin actions. Front Neuroendocrinol 2008; 29(2): 292-312.
[http://dx.doi.org/10.1016/j.yfrne.2008.01.001] [PMID: 18343488]
, 51Cai Z, Stocco C. Expression and regulation of progestin membrane receptors in the rat corpus luteum. Endocrinology 2005; 146(12): 5522-32.
[http://dx.doi.org/10.1210/en.2005-0759] [PMID: 16123161]
]. In rat corpus luteum, RDA 288 acts against apoptosis.

PGRMC1 contains a single transmembrane domain and a potential internal cytochrome b5-like heme/steroid-binding sequence [26Thomas P. Characteristics of membrane progestin receptor alpha (mPRalpha) and progesterone membrane receptor component 1 (PGMRC1) and their roles in mediating rapid progestin actions. Front Neuroendocrinol 2008; 29(2): 292-312.
[http://dx.doi.org/10.1016/j.yfrne.2008.01.001] [PMID: 18343488]
, 52Mir SU, Ahmed IS, Arnold S, Craven RJ. Elevated progesterone receptor membrane component 1/sigma-2 receptor levels in lung tumors and plasma from lung cancer patients. Int J Cancer 2012; 131(2): E1-9.
[http://dx.doi.org/10.1002/ijc.26432] [PMID: 21918976]
, 53Ahmed IS, Rohe HJ, Twist KE, Mattingly MN, Craven RJ. Progesterone receptor membrane component 1 (Pgrmc1): a heme-1 domain protein that promotes tumorigenesis and is inhibited by a small molecule. J Pharmacol Exp Ther 2010; 333(2): 564-73.
[http://dx.doi.org/10.1124/jpet.109.164210] [PMID: 20164297]
]. Both, PGRMC1 and the closely related PGRMC2 receptor, belong to the family of receptors associated with membranes (MAPR) [12Saint-Dizier M, Sandra O, Ployart S, Chebrout M, Constant F. Expression of nuclear progesterone receptor and progesterone receptor membrane components 1 and 2 in the oviduct of cyclic and pregnant cows during the post-ovulation period. Reprod Biol Endocrinol 2012; 10: 76.
[http://dx.doi.org/10.1186/1477-7827-10-76] [PMID: 22958265]
, 26Thomas P. Characteristics of membrane progestin receptor alpha (mPRalpha) and progesterone membrane receptor component 1 (PGMRC1) and their roles in mediating rapid progestin actions. Front Neuroendocrinol 2008; 29(2): 292-312.
[http://dx.doi.org/10.1016/j.yfrne.2008.01.001] [PMID: 18343488]
, 54Gerdes D, Wehling M, Leube B, Falkenstein E. Cloning and tissue expression of two putative steroid membrane receptors. Biol Chem 1998; 379(7): 907-11.
[PMID: 9705155]
]. Their homologues belonging to the MAPR genes family appear also in other Eucaryota, including nematodes, insects, yeast, and Arabidopsis thaliana. Another member of this family – neudesin, has been also identified in mammals [26Thomas P. Characteristics of membrane progestin receptor alpha (mPRalpha) and progesterone membrane receptor component 1 (PGMRC1) and their roles in mediating rapid progestin actions. Front Neuroendocrinol 2008; 29(2): 292-312.
[http://dx.doi.org/10.1016/j.yfrne.2008.01.001] [PMID: 18343488]
]. PGRMC1 is localized principally in the epithelium, within cell membrane, cytosol and nucleus, and also in endoplasmic reticulum and Golgi apparatus [12Saint-Dizier M, Sandra O, Ployart S, Chebrout M, Constant F. Expression of nuclear progesterone receptor and progesterone receptor membrane components 1 and 2 in the oviduct of cyclic and pregnant cows during the post-ovulation period. Reprod Biol Endocrinol 2012; 10: 76.
[http://dx.doi.org/10.1186/1477-7827-10-76] [PMID: 22958265]
, 55Wu W, Shi SQ, Huang HJ, Balducci J, Garfield RE. Changes in PGRMC1, a potential progesterone receptor, in human myometrium during pregnancy and labour at term and preterm. Mol Hum Reprod 2011; 17(4): 233-42.
[http://dx.doi.org/10.1093/molehr/gaq096] [PMID: 21131300]
]. Its expression has been demonstrated in many organs, i.e. uterus, liver, kidneys, adrenal glands and brain. It has been also identified in tissues involved in drug metabolism [56Schuster J, Karlsson T, Karlström PO, Poromaa IS, Dahl N. Down-regulation of progesterone receptor membrane component 1 (PGRMC1) in peripheral nucleated blood cells associated with premature ovarian failure (POF) and polycystic ovary syndrome (PCOS). Reprod Biol Endocrinol 2010; 8: 58.
[http://dx.doi.org/10.1186/1477-7827-8-58] [PMID: 20537145]
-58Bashour NM, Wray S. Progesterone directly and rapidly inhibits GnRH neuronal activity via progesterone receptor membrane component 1. Endocrinology 2012; 153(9): 4457-69.
[http://dx.doi.org/10.1210/en.2012-1122] [PMID: 22822163]
].

PGRMC1 displays moderately high affinity to P4. It constitutes the target also for other hormones, like glucocorticosteroids (corticosterone and cortisol) and 21-carbon steroids (testosterone). However, the affinity for P4 is about 2-10 times higher than for testosterone and glucocorticosteroids [26Thomas P. Characteristics of membrane progestin receptor alpha (mPRalpha) and progesterone membrane receptor component 1 (PGMRC1) and their roles in mediating rapid progestin actions. Front Neuroendocrinol 2008; 29(2): 292-312.
[http://dx.doi.org/10.1016/j.yfrne.2008.01.001] [PMID: 18343488]
]. PGRMC1 is capable of binding various molecules, like heme (its main known function), cholesterol and its metabolites, cytochrome P450 proteins, and many others [26Thomas P. Characteristics of membrane progestin receptor alpha (mPRalpha) and progesterone membrane receptor component 1 (PGMRC1) and their roles in mediating rapid progestin actions. Front Neuroendocrinol 2008; 29(2): 292-312.
[http://dx.doi.org/10.1016/j.yfrne.2008.01.001] [PMID: 18343488]
, 59Menzies GS, Howland K, Rae MT, Bramley TA. Stimulation of specific binding of [3H]-progesterone to bovine luteal cell-surface membranes: specificity of digitonin. Mol Cell Endocrinol 1999; 153(1-2): 57-69.
[http://dx.doi.org/10.1016/S0303-7207(99)00091-X] [PMID: 10459854]
]. Combined with the affinity to such functionally and morphologically different molecules, the relevant role of this receptor in the wide spectrum of processes, like steroid synthesis and metabolism, regulation of cholesterol conversion, axonal guidance, stress response, endocytosis, cellular homeostasis and influence on the reproductive behavior, has been indicated [15Gellersen B, Fernandes MS, Brosens JJ. Non-genomic progesterone actions in female reproduction. Hum Reprod Update 2009; 15(1): 119-38.
[http://dx.doi.org/10.1093/humupd/dmn044] [PMID: 18936037]
, 26Thomas P. Characteristics of membrane progestin receptor alpha (mPRalpha) and progesterone membrane receptor component 1 (PGMRC1) and their roles in mediating rapid progestin actions. Front Neuroendocrinol 2008; 29(2): 292-312.
[http://dx.doi.org/10.1016/j.yfrne.2008.01.001] [PMID: 18343488]
, 50Krebs CJ, Jarvis ED, Chan J, Lydon JP, Ogawa S, Pfaff DW. A membrane-associated progesterone-binding protein, 25-Dx, is regulated by progesterone in brain regions involved in female reproductive behaviors. Proc Natl Acad Sci USA 2000; 97(23): 12816-21.
[http://dx.doi.org/10.1073/pnas.97.23.12816] [PMID: 11070092]
, 60Cahill MA. Progesterone receptor membrane component 1: an integrative review. J Steroid Biochem Mol Biol 2007; 105(1-5): 16-36.
[http://dx.doi.org/10.1016/j.jsbmb.2007.02.002] [PMID: 17583495]
]. Some drugs, for instance, haloperidol competes with endogenous P4 in binding to PGRMC1, while P4 binding is inhibited by such drugs as fluphenazine or carbapentane citrate [26Thomas P. Characteristics of membrane progestin receptor alpha (mPRalpha) and progesterone membrane receptor component 1 (PGMRC1) and their roles in mediating rapid progestin actions. Front Neuroendocrinol 2008; 29(2): 292-312.
[http://dx.doi.org/10.1016/j.yfrne.2008.01.001] [PMID: 18343488]
]. This makes the receptor and the associated proteins an attractive target of numerous, especially oncological therapies, firstly - due to high affinity to steroids and drugs, secondly - due to their activity promoting neoplastic cells survival. Hormonal regulation of PGRMC1 expression is tissue-specific.

Many of described activities and functions of PGRMC1 both, in reproductive system and other tissues and organs, like central nervous system are obtained from the studies on animals with PGRMC1 gene knockout [50Krebs CJ, Jarvis ED, Chan J, Lydon JP, Ogawa S, Pfaff DW. A membrane-associated progesterone-binding protein, 25-Dx, is regulated by progesterone in brain regions involved in female reproductive behaviors. Proc Natl Acad Sci USA 2000; 97(23): 12816-21.
[http://dx.doi.org/10.1073/pnas.97.23.12816] [PMID: 11070092]
, 58Bashour NM, Wray S. Progesterone directly and rapidly inhibits GnRH neuronal activity via progesterone receptor membrane component 1. Endocrinology 2012; 153(9): 4457-69.
[http://dx.doi.org/10.1210/en.2012-1122] [PMID: 22822163]
]. In the nervous system, PGRMC1 has been identified in hypothalamus, circumventricular organs, ependyma of the lateral ventricles and meninges, structures directly involved in the production of the cerebrospinal fluid, and osmoregulation. In rats, PGRMC1/25 D-x is expressed in cerebellum and displays age-dependence: moderate expression in young individuals, mainly in Purkinje cells and cells of the granular layer, and low expression in mature individuals, only in Purkinje cells. This expression appears to be sex-independent [26Thomas P. Characteristics of membrane progestin receptor alpha (mPRalpha) and progesterone membrane receptor component 1 (PGMRC1) and their roles in mediating rapid progestin actions. Front Neuroendocrinol 2008; 29(2): 292-312.
[http://dx.doi.org/10.1016/j.yfrne.2008.01.001] [PMID: 18343488]
]. PGRMC1 displays pleiotropic activity. It affects Schwann cell proliferation, and myelinization, synaptogenesis, memory and cognitive processes, neuronal excitability, glial function, and progenitor cell proliferation [61Garay LI, González Deniselle MC, Brocca ME, Lima A, Roig P, De Nicola AF. Progesterone down-regulates spinal cord inflammatory mediators and increases myelination in experimental autoimmune encephalomyelitis. Neuroscience 2012; 226: 40-50.
[http://dx.doi.org/10.1016/j.neuroscience.2012.09.032] [PMID: 23000619]
-63Cooke PS, Nanjappa MK, Yang Z, Wang KK. Therapeutic effects of progesterone and its metabolites in traumatic brain injury may involve non-classical signaling mechanisms. Front Neurosci 2013; 7: 108.
[http://dx.doi.org/10.3389/fnins.2013.00108] [PMID: 23781171]
]. Furthermore, PGRMC1 most likely mediates neuroprotective action of P4, thus its expression increases after brain injury and it induces synthesis of brain-derived neurotrophic factor (BDNF) in glial cells [63Cooke PS, Nanjappa MK, Yang Z, Wang KK. Therapeutic effects of progesterone and its metabolites in traumatic brain injury may involve non-classical signaling mechanisms. Front Neurosci 2013; 7: 108.
[http://dx.doi.org/10.3389/fnins.2013.00108] [PMID: 23781171]
, 64Gimpl G, Wiegand V, Burger K, Fahrenholz F. Cholesterol and steroid hormones: modulators of oxytocin receptor function. Prog Brain Res 2002; 139: 43-55.
[http://dx.doi.org/10.1016/S0079-6123(02)39006-X] [PMID: 12436925]
]. It has been proven that P4 and its metabolites decrease cerebral edema, have beneficial influence on blood-brain barrier function and intracranial pressure, and shorten recuperation time after brain damage as far as restored cognitive and behavioral functions are concerned [63Cooke PS, Nanjappa MK, Yang Z, Wang KK. Therapeutic effects of progesterone and its metabolites in traumatic brain injury may involve non-classical signaling mechanisms. Front Neurosci 2013; 7: 108.
[http://dx.doi.org/10.3389/fnins.2013.00108] [PMID: 23781171]
]. Also, neudesin exhibits neurotrophic activity. It binds with heme and directly stimulates MAP kinase and neuronal signalization and activity [53Ahmed IS, Rohe HJ, Twist KE, Mattingly MN, Craven RJ. Progesterone receptor membrane component 1 (Pgrmc1): a heme-1 domain protein that promotes tumorigenesis and is inhibited by a small molecule. J Pharmacol Exp Ther 2010; 333(2): 564-73.
[http://dx.doi.org/10.1124/jpet.109.164210] [PMID: 20164297]
]. That activity is believed to be mediated by membrane receptors [63Cooke PS, Nanjappa MK, Yang Z, Wang KK. Therapeutic effects of progesterone and its metabolites in traumatic brain injury may involve non-classical signaling mechanisms. Front Neurosci 2013; 7: 108.
[http://dx.doi.org/10.3389/fnins.2013.00108] [PMID: 23781171]
].

PGRMC and its homologues regulate cholesterol synthesis through cytochrome P450, Cyp51 (lanosterol demethylase) activation, what plays a key role in cardiovascular diseases. PGRMC1 participation is also suggested in metabolism of drugs, hormones and lipids. The aspect of regulation of cholesterol concentration is especially important here [26Thomas P. Characteristics of membrane progestin receptor alpha (mPRalpha) and progesterone membrane receptor component 1 (PGMRC1) and their roles in mediating rapid progestin actions. Front Neuroendocrinol 2008; 29(2): 292-312.
[http://dx.doi.org/10.1016/j.yfrne.2008.01.001] [PMID: 18343488]
]. It is also known that P4 affects the signal transduction and subdomain localization of receptors via its influence on cholesterol trafficking. Since cholesterol-rich rafts are considered to be organization centers for cellular signal transduction, changes of cholesterol concentration or distribution may have profound effects on receptor-mediated signaling in general. This mechanism has been shown to underpin the inhibitory effects of P4 on OTR (oxytocin receptor) signaling, not competitive binding to the receptor itself [64Gimpl G, Wiegand V, Burger K, Fahrenholz F. Cholesterol and steroid hormones: modulators of oxytocin receptor function. Prog Brain Res 2002; 139: 43-55.
[http://dx.doi.org/10.1016/S0079-6123(02)39006-X] [PMID: 12436925]
].

In the process of regulation of cholesterol concentration, PGRMC1 creates complexes with proteins, e.g. Scap (SREBP-cleavage activating protein) and Insig1 (Insulin-induced gene) [26Thomas P. Characteristics of membrane progestin receptor alpha (mPRalpha) and progesterone membrane receptor component 1 (PGMRC1) and their roles in mediating rapid progestin actions. Front Neuroendocrinol 2008; 29(2): 292-312.
[http://dx.doi.org/10.1016/j.yfrne.2008.01.001] [PMID: 18343488]
]. After their synthesis in the endoplasmic reticulum, transcriptional factors, which activate genes encoding enzymes necessary for lipid synthesis SREBPs (Sterol Regulatory Element-binding Protein), bind to the Scap protein [15Gellersen B, Fernandes MS, Brosens JJ. Non-genomic progesterone actions in female reproduction. Hum Reprod Update 2009; 15(1): 119-38.
[http://dx.doi.org/10.1093/humupd/dmn044] [PMID: 18936037]
]. In the case of sufficient cholesterol concentration, Insig-1 forms a complex with Scap, what facilitates retention of the Scap/SREBP protein complex in the endoplasmic reticulum. In turn, in case of cell deprivation of sterols, Scap regulates the transport of SREBPs from the endoplasmic reticulum to the Golgi apparatus, where the complex is subjected to proteolysis. This event enables SREBPs migration to the nucleus and leads to the transactivation of genes involved in cholesterol synthesis. The fact that PGRMC1 binds, both Insig-1 and Scap, confirms its localization in the endoplasmic reticulum and suggests that its function could be ‘sterol detection’ [15Gellersen B, Fernandes MS, Brosens JJ. Non-genomic progesterone actions in female reproduction. Hum Reprod Update 2009; 15(1): 119-38.
[http://dx.doi.org/10.1093/humupd/dmn044] [PMID: 18936037]
, 26Thomas P. Characteristics of membrane progestin receptor alpha (mPRalpha) and progesterone membrane receptor component 1 (PGMRC1) and their roles in mediating rapid progestin actions. Front Neuroendocrinol 2008; 29(2): 292-312.
[http://dx.doi.org/10.1016/j.yfrne.2008.01.001] [PMID: 18343488]
, 53Ahmed IS, Rohe HJ, Twist KE, Mattingly MN, Craven RJ. Progesterone receptor membrane component 1 (Pgrmc1): a heme-1 domain protein that promotes tumorigenesis and is inhibited by a small molecule. J Pharmacol Exp Ther 2010; 333(2): 564-73.
[http://dx.doi.org/10.1124/jpet.109.164210] [PMID: 20164297]
].

PGRMC1 is induced by different carcinogens, including dioxins. It is up-regulated in many types of malignant tumors, where it promotes cell survival and determines their resistance to damage and also affects tumor vascularization [52Mir SU, Ahmed IS, Arnold S, Craven RJ. Elevated progesterone receptor membrane component 1/sigma-2 receptor levels in lung tumors and plasma from lung cancer patients. Int J Cancer 2012; 131(2): E1-9.
[http://dx.doi.org/10.1002/ijc.26432] [PMID: 21918976]
, 53Ahmed IS, Rohe HJ, Twist KE, Mattingly MN, Craven RJ. Progesterone receptor membrane component 1 (Pgrmc1): a heme-1 domain protein that promotes tumorigenesis and is inhibited by a small molecule. J Pharmacol Exp Ther 2010; 333(2): 564-73.
[http://dx.doi.org/10.1124/jpet.109.164210] [PMID: 20164297]
, 65Su C, Cunningham RL, Rybalchenko N, Singh M. Progesterone increases the release of brain-derived neurotrophic factor from glia via progesterone receptor membrane component 1 (Pgrmc1)-dependent ERK5 signaling. Endocrinology 2012; 153(9): 4389-400.
[http://dx.doi.org/10.1210/en.2011-2177] [PMID: 22778217]
-69Selmin O, Thorne PA, Blachere FM, Johnson PD, Romagnolo DF. Transcriptional activation of the membrane-bound progesterone receptor (mPR) by dioxin, in endocrine-responsive tissues. Mol Reprod Dev 2005; 70(2): 166-74.
[http://dx.doi.org/10.1002/mrd.20090] [PMID: 15570619]
]. The PGRMC1 expression is augmented by chemotherapy, and also in mouse cells with short telomeres and impaired chromosomes. Thus, the hypothesis has been made that DNA damage is followed by an increase in the receptor expression, and it plays a role in neoplastic promotion. The protein receptor overexpression has been demonstrated in carcinoma of breast, colon, thyroid gland, lungs, cervix and ovary, what suggests its potential role as a marker for neoplasia [49Peluso JJ. Progesterone signaling mediated through progesterone receptor membrane component-1 in ovarian cells with special emphasis on ovarian cancer. Steroids 2011; 76(9): 903-9.
[PMID: 21371489]
, 52Mir SU, Ahmed IS, Arnold S, Craven RJ. Elevated progesterone receptor membrane component 1/sigma-2 receptor levels in lung tumors and plasma from lung cancer patients. Int J Cancer 2012; 131(2): E1-9.
[http://dx.doi.org/10.1002/ijc.26432] [PMID: 21918976]
, 70Causey MW, Huston LJ, Harold DM, et al. Transcriptional analysis of novel hormone receptors PGRMC1 and PGRMC2 as potential biomarkers of breast adenocarcinoma staging. J Surg Res 2011; 171(2): 615-22.
[http://dx.doi.org/10.1016/j.jss.2010.04.034] [PMID: 20655063]
]. In this process, binding PGRMC1 with EGFR could constitute a key point. Simultaneously, EGFR inhibitors, e.g. erlotinib/tarceva and tyrphostin/AG-1478 could be effective in antineoplastic therapy [66Ahmed IS, Rohe HJ, Twist KE, Craven RJ. Pgrmc1 (progesterone receptor membrane component 1) associates with epidermal growth factor receptor and regulates erlotinib sensitivity. J Biol Chem 2010; 285(32): 24775-82.
[http://dx.doi.org/10.1074/jbc.M110.134585] [PMID: 20538600]
].

Significantly less is known about PGRMC2, although it seems that, similarly to PGRMC1, it is necessary for proper function of the reproductive system. It has been proven in macaques that during the secretory phase, mRNA and PGRMC2 protein are expressed in functional layer of endometrium, principally within the luminal and glandular epithelium, what corresponds with simultaneous lack of PGRMC1 and nPR in these locations. It suggests that P4 could participate in embryo implantation precisely due to PGRMC2 [43Pru JK, Clark NC. PGRMC1 and PGRMC2 in uterine physiology and disease. Front Neurosci 2013; 7: 168.
[http://dx.doi.org/10.3389/fnins.2013.00168] [PMID: 24065879]
]. In turn, through PGRMC1 activation, P4 allows the maintenance of pregnancy, thus suppressing premature uterine contractile activity and affecting the vascular bed of the placenta. Decreased expression of this membrane receptor seems to be one of the key factors necessary for the initiation of parturition [55Wu W, Shi SQ, Huang HJ, Balducci J, Garfield RE. Changes in PGRMC1, a potential progesterone receptor, in human myometrium during pregnancy and labour at term and preterm. Mol Hum Reprod 2011; 17(4): 233-42.
[http://dx.doi.org/10.1093/molehr/gaq096] [PMID: 21131300]
, 71Slonina D, Kowalik MK, Kotwica J. Expression of progesterone receptor membrane component 1, serpine mRNA binding protein 1 and nuclear progesterone receptor isoforms A and B in the bovine myometrium during the estrous cycle and early pregnancy. J Reprod Dev 2012; 58(3): 288-94.
[http://dx.doi.org/10.1262/jrd.11-052T] [PMID: 22277931]
]. PGRMC1 with PGRMC2 are probably involved in the functioning of oviduct smooth muscles, and they form a proper environment conducive to conception and oocyte transport, what has been proven already in cows [12Saint-Dizier M, Sandra O, Ployart S, Chebrout M, Constant F. Expression of nuclear progesterone receptor and progesterone receptor membrane components 1 and 2 in the oviduct of cyclic and pregnant cows during the post-ovulation period. Reprod Biol Endocrinol 2012; 10: 76.
[http://dx.doi.org/10.1186/1477-7827-10-76] [PMID: 22958265]
]. In males, both isoforms could mediate in the acrosome reaction induced by P4 [26Thomas P. Characteristics of membrane progestin receptor alpha (mPRalpha) and progesterone membrane receptor component 1 (PGMRC1) and their roles in mediating rapid progestin actions. Front Neuroendocrinol 2008; 29(2): 292-312.
[http://dx.doi.org/10.1016/j.yfrne.2008.01.001] [PMID: 18343488]
, 72Lösel R, Breiter S, Seyfert M, Wehling M, Falkenstein E. Classic and non-classic progesterone receptors are both expressed in human spermatozoa. Horm Metab Res 2005; 37(1): 10-4.
[http://dx.doi.org/10.1055/s-2005-861023] [PMID: 15702432]
].

3.3. Non-classical Activity

Three mechanisms involved in the activation of non-classical pathway have been suggested. Many aspects still remain unresolved and only single pathways, through which progestagens could realize their actions, are being analyzed in different species. Mediation of G-proteins, including typical α subunit dissociation from subunits β and γ, is the common reference for these pathways. The first mechanism assumes that progestagens activate MAPK kinases, e.g. Akt/PI 3, probably through G-protein βγ subunits (it has been proven in case of mPRα and mPRβ in fish), what results in Erk1/2 phosphorylation, leading to changes in gene transcription [26Thomas P. Characteristics of membrane progestin receptor alpha (mPRalpha) and progesterone membrane receptor component 1 (PGMRC1) and their roles in mediating rapid progestin actions. Front Neuroendocrinol 2008; 29(2): 292-312.
[http://dx.doi.org/10.1016/j.yfrne.2008.01.001] [PMID: 18343488]
, 73Pace MC, Thomas P. Steroid-induced oocyte maturation in Atlantic croaker (Micropogonias undulatus) is dependent on activation of the phosphatidylinositol 3-kinase/Akt signal transduction pathway. Biol Reprod 2005; 73(5): 988-96.
[http://dx.doi.org/10.1095/biolreprod.105.041400] [PMID: 16014813]
]. The second mechanism underlines the role of one of the MAPK – p38, in which mPRα activation in the myometrium leads to phosphorylation of myosin light chains [26Thomas P. Characteristics of membrane progestin receptor alpha (mPRalpha) and progesterone membrane receptor component 1 (PGMRC1) and their roles in mediating rapid progestin actions. Front Neuroendocrinol 2008; 29(2): 292-312.
[http://dx.doi.org/10.1016/j.yfrne.2008.01.001] [PMID: 18343488]
]. The third path includes a suppression of adenylate cyclase activity. It is also mediated by progestagens/mPRα signalization and subunit α of the inhibitory Gi protein. As a result of cyclase inhibition, the concentration of cAMP decreases [36Dosiou C, Hamilton AE, Pang Y, et al. Expression of membrane progesterone receptors on human T lymphocytes and Jurkat cells and activation of G-proteins by progesterone. J Endocrinol 2008; 196(1): 67-77.
[http://dx.doi.org/10.1677/JOE-07-0317] [PMID: 18180318]
, 47Peluso JJ. Multiplicity of progesterones actions and receptors in the mammalian ovary. Biol Reprod 2006; 75(1): 2-8.
[http://dx.doi.org/10.1095/biolreprod.105.049924] [PMID: 16452458]
, 74Singh M, Su C, Ng S. Non-genomic mechanisms of progesterone action in the brain. Front Neurosci 2013; 7: 159.
[http://dx.doi.org/10.3389/fnins.2013.00159] [PMID: 24065876]
]. However, in the process of activation of this path, the stimulatory G-protein is also involved (Gs), which could lead to increased cAMP concentration (e.g. in spermatozoa of Genyonemus lineatus). In the course of non-genomic pathway induction through mPRα and mPRβ, transactivation of the nuclear receptor and expression of steroid receptor co-activator - SRC2 within the human myometrium becomes impaired [26Thomas P. Characteristics of membrane progestin receptor alpha (mPRalpha) and progesterone membrane receptor component 1 (PGMRC1) and their roles in mediating rapid progestin actions. Front Neuroendocrinol 2008; 29(2): 292-312.
[http://dx.doi.org/10.1016/j.yfrne.2008.01.001] [PMID: 18343488]
].

4. HOW BOTH GENOMIC AND EXTRAGENOMIC PATHWAYS COULD AFFECT ONE ANOTHER?

In all likelihood, classical and non-classical pathways could functionally cross, and nuclear and membrane fractions of receptors could cooperate with one another. The first proof for ‘cross-talk’ between mPR and nPR is based on the fact that mPR activation through P4 leads to nPRB transactivation. Additionally, mPR activation results in decreased concentration of steroid receptor co-activator 2 [75Karteris E, Zervou S, Pang Y, et al. Progesterone signaling in human myometrium through two novel membrane G protein-coupled receptors: potential role in functional progesterone withdrawal at term. Mol Endocrinol 2006; 20(7): 1519-34.
[http://dx.doi.org/10.1210/me.2005-0243] [PMID: 16484338]
]. The process of initiation of parturition is an example of a cooperation between membrane and nuclear fractions of P4 receptors. The decrease in progestagen concentration is crucial for labor initiation in numerous mammal species [75Karteris E, Zervou S, Pang Y, et al. Progesterone signaling in human myometrium through two novel membrane G protein-coupled receptors: potential role in functional progesterone withdrawal at term. Mol Endocrinol 2006; 20(7): 1519-34.
[http://dx.doi.org/10.1210/me.2005-0243] [PMID: 16484338]
, 76Falkenstein E, Heck M, Gerdes D, et al. Specific progesterone binding to a membrane protein and related nongenomic effects on Ca2+-fluxes in sperm. Endocrinology 1999; 140(12): 5999-6002.
[http://dx.doi.org/10.1210/endo.140.12.7304] [PMID: 10579369]
]. However, a different mechanism, namely the decrease in P4 receptors expression, has been proposed in humans. Normally, PGRMC1 receptor synthesis increases in the course of pregnancy and decreases during parturition. Moreover, its inadequate decrease in the expression could lead to preterm delivery [55Wu W, Shi SQ, Huang HJ, Balducci J, Garfield RE. Changes in PGRMC1, a potential progesterone receptor, in human myometrium during pregnancy and labour at term and preterm. Mol Hum Reprod 2011; 17(4): 233-42.
[http://dx.doi.org/10.1093/molehr/gaq096] [PMID: 21131300]
]. In case of nPR, and especially nPRB, the situation is similar: the expression of this receptor in primates also decreases. The nPRA isoform, which is up-regulated in the myometrium during labor and could suppress transcriptional activity of nPRB, is the potential mediator in this phenomenon.

Another suggested mechanism is that progestagens influence the myometrium through a non-classical pathway with the participation of mPR [77Bartlett SR, Sawdy R, Mann GE. Induction of cyclooxygenase-2 expression in human myometrial smooth muscle cells by interleukin-1beta: involvement of p38 mitogen-activated protein kinase. J Physiol 1999; 520(Pt 2): 399-406.
[http://dx.doi.org/10.1111/j.1469-7793.1999.00399.x] [PMID: 10523409]
]. In early stages of pregnancy, nPRB predominates in the human myometrium and acts synergistically with mPR. nPRB transactivation is the result of subunit Gi activation. Simultaneously, circulating sex steroids up-regulate both, mPRα and mPRβ. In turn, mPR activation at the end of pregnancy leads to SRC2 down-regulation, what together with changed nPRB/nPRA balance leads to a decrease of nPRB transcriptional activity in the myometrium [75Karteris E, Zervou S, Pang Y, et al. Progesterone signaling in human myometrium through two novel membrane G protein-coupled receptors: potential role in functional progesterone withdrawal at term. Mol Endocrinol 2006; 20(7): 1519-34.
[http://dx.doi.org/10.1210/me.2005-0243] [PMID: 16484338]
, 77Bartlett SR, Sawdy R, Mann GE. Induction of cyclooxygenase-2 expression in human myometrial smooth muscle cells by interleukin-1beta: involvement of p38 mitogen-activated protein kinase. J Physiol 1999; 520(Pt 2): 399-406.
[http://dx.doi.org/10.1111/j.1469-7793.1999.00399.x] [PMID: 10523409]
]. As a result, mPR cannot activate nPRB. This cascade of reactions enables P4 to act preferentially for mPRs during parturition in order to suppress adenylate cyclase activity, leading to smooth muscle phosphorylation and subsequent contractions [78Fu X, Rezapour M, Löfgren M, Ulmsten U, Bäckström T. Unexpected stimulatory effect of progesterone on human myometrial contractile activity in vitro. Obstet Gynecol 1993; 82(1): 23-8.
[PMID: 8515921]
]. cAMP, the second messenger formed by adenylate cyclase from ATP, is the universal signal in the cross-talk between nuclear and membrane receptors. It subsequently activates PKA, leading to CREB phosphorylation [4Losel RM, Falkenstein E, Feuring M, et al. Nongenomic steroid action: controversies, questions, and answers. Physiol Rev 2003; 83(3): 965-1016.
[http://dx.doi.org/10.1152/physrev.00003.2003] [PMID: 12843413]
]. This, in turn, activates MAPK pathway, resulting in SRC1 phosphorylation. The phosphorylated forms of pCREB and pSRC1 cooperate in steroid receptor activation. Other mediators, which regulate the cross-talk between steroid receptors, are proline, glutamine acid, leucine-rich protein 1, or paxillinproteins [1Hammes SR, Levin ER. Minireview: Recent advances in extranuclear steroid receptor actions. Endocrinology 2011; 152(12): 4489-95.
[http://dx.doi.org/10.1210/en.2011-1470] [PMID: 22028449]
].

Classical nPR receptors could mediate P4 activity also through the non-genomic pathway. For instance, human nPRB contains poliproline motif in the amino acid domain, which interacts with SH3 domain of Src. In this way, cytoplasmic PR could mediate P4-induced rapid activation of c-Src and downstream Ras/Raf/ERK1/2, independently of its transcriptional activity. Activation of the MAPK pathway invariably leads to phosphorylation of the following transcriptional factors: c-Fos, c-Jun and nPR [74Singh M, Su C, Ng S. Non-genomic mechanisms of progesterone action in the brain. Front Neurosci 2013; 7: 159.
[http://dx.doi.org/10.3389/fnins.2013.00159] [PMID: 24065876]
].

5. SUMMARY

Membrane receptors mediate a wide spectrum of processes in the body, e.g. acrosome reaction, oocytes maturation, autocrine activity in the corpus luteum, steroid and cholesterol metabolism, cellular homeostasis, neuronal excitability, neuroendocrine effects, behavioral processes, and response to stress. The receptors are situated in many tissues and organs, displaying a predilection to specific localizations, what has a special significance in both, morphologic and physiologic aspects. The cooperation between nuclear and membrane fractions of P4 receptors plays a relevant role. Thus it seems safe to hypothesize that membrane receptors are necessary in a number of processes for specific fulfillment of the activity initiated by nuclear receptors. Taking into consideration a broad distribution and significance of non-classical pathways and membrane receptors, the aspect of receptor stimulation or inhibition could be useful in treating multiple pathologies, e.g. some forms of infertility [1Hammes SR, Levin ER. Minireview: Recent advances in extranuclear steroid receptor actions. Endocrinology 2011; 152(12): 4489-95.
[http://dx.doi.org/10.1210/en.2011-1470] [PMID: 22028449]
, 46Hanna R, Pang Y, Thomas P, Zhu Y. Cell-surface expression, progestin binding, and rapid nongenomic signaling of zebrafish membrane progestin receptors alpha and beta in transfected cells. J Endocrinol 2006; 190(2): 247-60.
[http://dx.doi.org/10.1677/joe.1.06694] [PMID: 16899559]
].

Plenty of aspects regarding membrane receptors and non-classical pathways are still uncovered or controversial. Despite a great number of PGRMC1 function aspects which have been described so far, some authors hypothesize that this receptor could play a role as an adaptor protein, accompanying mPR transport to the cell surface. What is relevant, the same hormone could induce different effects in various species through non-classical pathway, or the same result could be achieved by different steroids. Controversies regarding membrane pathway could stem just from this diversity and heterogeneity [8Ahmad N, Kumar R. Steroid hormone receptors in cancer development: a target for cancer therapeutics. Cancer Lett 2011; 300(1): 1-9.
[http://dx.doi.org/10.1016/j.canlet.2010.09.008] [PMID: 20926181]
]. Both, visualization of levels on which nuclear and membrane fractions of the receptors could reciprocally work, and recognition of every cell and tissue where membrane receptors are expressed, might enable a new, innovative look at processes which, although known, remain elusive [79Sołtysik K, Czekaj P, Suszka-Świtek A, Kociszewska K, Plewka D. Changes in the subcellular and tissue location of estrogen and progesterone receptors in rat uterus after long-term treatment with analogs of gonadoliberin. Ginekol Pol 2014; 85(4): 254-63.
[http://dx.doi.org/10.17772/gp/1721] [PMID: 24834702]
].

LIST OF ABBREVIATIONS

CNS  = Central Nervous System
GR  = Glucocorticoid Receptor
HRE  = Hormone Response Element
HSP  = Chaperone Proteins
PAQR  = Progesterone Adiponectin Q Receptor
PGRMC1  = Progesterone Receptor Membrane Component One
P4  = Progesterone
PR  = Progesterone Receptor
mPR  = Membrane Progesterone Receptors
nPR  = Nuclear Progesterone Receptors

CONFLICT OF INTEREST

The authors confirm that this article content has no conflict of interest.

ACKNOWLEDGEMENTS

Declared none.

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Debomoy K. Lahiri
(Indiana University School of Medicine, USA)

"Open access journals represent a major break-through in publishing. They provide easy access to the latest research on a wide variety of issues. Relevant and timely articles are made available in a fraction of the time taken by more conventional publishers. Articles are of uniformly high quality and written by the world's leading authorities."


Robert Looney
(Naval Postgraduate School, USA)

"Open access journals have transformed the way scientific data is published and disseminated: particularly, whilst ensuring a high quality standard and transparency in the editorial process, they have increased the access to the scientific literature by those researchers that have limited library support or that are working on small budgets."


Richard Reithinger
(Westat, USA)

"Not only do open access journals greatly improve the access to high quality information for scientists in the developing world, it also provides extra exposure for our papers."


J. Ferwerda
(University of Oxford, UK)

"Open Access 'Chemistry' Journals allow the dissemination of knowledge at your finger tips without paying for the scientific content."


Sean L. Kitson
(Almac Sciences, Northern Ireland)

"In principle, all scientific journals should have open access, as should be science itself. Open access journals are very helpful for students, researchers and the general public including people from institutions which do not have library or cannot afford to subscribe scientific journals. The articles are high standard and cover a wide area."


Hubert Wolterbeek
(Delft University of Technology, The Netherlands)

"The widest possible diffusion of information is critical for the advancement of science. In this perspective, open access journals are instrumental in fostering researches and achievements."


Alessandro Laviano
(Sapienza - University of Rome, Italy)

"Open access journals are very useful for all scientists as they can have quick information in the different fields of science."


Philippe Hernigou
(Paris University, France)

"There are many scientists who can not afford the rather expensive subscriptions to scientific journals. Open access journals offer a good alternative for free access to good quality scientific information."


Fidel Toldrá
(Instituto de Agroquimica y Tecnologia de Alimentos, Spain)

"Open access journals have become a fundamental tool for students, researchers, patients and the general public. Many people from institutions which do not have library or cannot afford to subscribe scientific journals benefit of them on a daily basis. The articles are among the best and cover most scientific areas."


M. Bendandi
(University Clinic of Navarre, Spain)

"These journals provide researchers with a platform for rapid, open access scientific communication. The articles are of high quality and broad scope."


Peter Chiba
(University of Vienna, Austria)

"Open access journals are probably one of the most important contributions to promote and diffuse science worldwide."


Jaime Sampaio
(University of Trás-os-Montes e Alto Douro, Portugal)

"Open access journals make up a new and rather revolutionary way to scientific publication. This option opens several quite interesting possibilities to disseminate openly and freely new knowledge and even to facilitate interpersonal communication among scientists."


Eduardo A. Castro
(INIFTA, Argentina)

"Open access journals are freely available online throughout the world, for you to read, download, copy, distribute, and use. The articles published in the open access journals are high quality and cover a wide range of fields."


Kenji Hashimoto
(Chiba University, Japan)

"Open Access journals offer an innovative and efficient way of publication for academics and professionals in a wide range of disciplines. The papers published are of high quality after rigorous peer review and they are Indexed in: major international databases. I read Open Access journals to keep abreast of the recent development in my field of study."


Daniel Shek
(Chinese University of Hong Kong, Hong Kong)

"It is a modern trend for publishers to establish open access journals. Researchers, faculty members, and students will be greatly benefited by the new journals of Bentham Science Publishers Ltd. in this category."


Jih Ru Hwu
(National Central University, Taiwan)


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