Membrane progesterone receptor

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Membrane progesterone receptors (mPRs) are a group of cell surface receptors and membrane steroid receptors belonging to the progestin and adipoQ receptor (PAQR) family which bind the endogenous progestogen and neurosteroid progesterone, as well as the neurosteroid allopregnanolone. [1] [2] Unlike the progesterone receptor (PR), a nuclear receptor which mediates its effects via genomic mechanisms, mPRs are cell surface receptors which rapidly alter cell signaling via modulation of intracellular signaling cascades. [1] The mPRs mediate important physiological functions in male and female reproductive tracts, liver, neuroendocrine tissues, and the immune system as well as in breast and ovarian cancer.

Contents

The mPRs appear to be involved in the neuroprotective and antigonadotropic effects of progesterone and allopregnanolone. [1] [2] The progesterone active metabolites 5α-dihydroprogesterone, also a progestogen, and allopregnanolone, which are positive allosteric modulators of the GABAA receptor, have been found to rapidly influence sexual receptivity and behavior in mice, actions that are GABAA receptor-dependent. [3] [4]

These proteins are classified into three groups known as mPRα (PAQR7), mPRβ (PAQR8), mPRγ (PAQR5), mPRδ (PAQR6), and mPRϵ (PAQR9).

mPR Subtypes

mPRα

mPRa structure. This image is based on the following table. Membrane-progesterone-receptor-alpha.png
mPRα structure. This image is based on the following table.

Membrane progesterone receptor alpha (mPRα) is a protein that in humans is encoded by the PAQR7 gene. [6] It is a steroid receptor which binds progesterone in vitro. Recent studies suggest the mPRα has important physiological functions in a variety of reproductive tissues. The mPRα is an intermediary in progestin induction of oocyte maturation and stimulation of sperm hyper motility in fish. In mammals, the mPRα has been implied in progesterone regulation of uterine functions in humans and GnRH secretion in rodents. [7]

mPRβ

mPRb structure. This image is based on the following table. Membrane-progesterone-receptor-beta.png
mPRβ structure. This image is based on the following table.

Membrane progesterone receptor beta (mPRβ) is a protein that in humans is encoded by the PAQR8 gene. [9]

A recent study [10] has investigated the role of mPRβ in regulating in vitro maturation (IVM) of pig cumulus-oocyte complexes (COCs). This study suggests that the mPRβ is a molecule related to cumulus expansion and it might function by regulation of exocytosis. The conclusion of this study is that mPRβ might play an important role on the function of the protein.

mPRγ

mPRg structure. This image is based on the following table. Membrane-progesterone-receptor-gamma.png
mPRγ structure. This image is based on the following table.

Membrane progesterone receptor gamma (mPRγ) is a protein that in humans is encoded by the PAQR5 gene. [12]

A study about the mPRγ subtype [13] has generated an antibody against this receptor in order to explore the role of mPRγ. Scientists found that mPRγ is expressed in female mouse reproductive tissues such as ovary and fallopian tube, and also in the lung and liver of both sexes. Immunohistochemical studies revealed that mPRγ is associated with the apical membrane of ciliated cells in the lumen of the fallopian tube, including human cells. That suggests a common role for mPRγ in the regulation of ciliary activity in the fallopian tube and the gamete transport in mammals. The presence of mPRγ in lung and liver of mice indicates that the receptor mediates the actions of progesterone outside the reproductive tract as well.

mPRδ

Membrane progesterone receptor delta (mPRδ) is a protein that in humans is encoded by the PAQR6 gene. [14]

mPRϵ

Membrane progesterone receptor epsilon (mPRϵ) is a protein that in humans is encoded by the PAQR9 gene. [15]

Summary table of features

Family members include: [16]

mPR subtypeGeneLengthMass (Da)Tissue specificity
mPRα PAQR7 34639,719Ovary, testis, placenta, uterus, bladder, others [17]
mPRβ PAQR8 35440,464Brain, spinal cord, kidney, testis, others [17]
mPRγ PAQR5 33038,014Brain, lung, kidney, colon, adrenal, others [17]
mPRδ PAQR6 34437,989Brain, breast, others [17] [18]
mPRϵ PAQR9 37742,692Brain, breast, others [17] [18]

The general functions of these subtypes of mPR are: being steroid membrane receptors and binding progesterone. They also may be involved in oocyte maturation.

Potential roles

Membrane progesterone receptors can independently activate signaling pathways in cells. As seen in the example above, progesterone augmented cAMP levels increase cyclic AMP response element (CRE) transcriptional activity.This image is based on the following figure. Mpr pathway example.png
Membrane progesterone receptors can independently activate signaling pathways in cells. As seen in the example above, progesterone augmented cAMP levels increase cyclic AMP response element (CRE) transcriptional activity.This image is based on the following figure.

The discovery of a membrane located progesterone receptor (mPR) unrelated to the classical progesterone receptor (PR) in fish ovaries and its subsequent identification in mammal tissues suggests that mPRs could be a potential mediator of non-traditional progesterone actions, particularly in tissues where PR is absent. Even though classical PRs and mPRs can also have overlapping regional expression (e.g., both are expressed in the hippocampus, cortex, hypothalamus and cerebellum), their ligand specificity is not identical (for example mPRs bind to 17α-hydroxyprogesterone and 5-dihydroprogesterone with greater affinity than to the classical PRs). [19] [20]

Many of progesterone's actions are too fast to be readily explained by a genomic mechanism which typically occurs over a time scale of hours – like most of the classical functions of progesterone mediated by progesterone receptors PR-A and PR-B, which mediate progesterone’s regulation of diverse female vertebrate reproductive functions through altering gene transcription – and it is now widely accepted that progesterone can also exert fast cell surface-initiated actions within minutes through activation of membrane receptors and their associated intracellular signaling paths. [1]

While some of the alternative progesterone actions are nongenomic, others may ultimately lead to altered gene transcription involving the activation of second messengers (such as MAP kinases) and through the alteration of progesterone receptors transactivation through effects on coactivators (such as SRC2). [1]

Extensive evidence has been obtained by different research groups that wild-type mPRs in a wide range of vertebrate cells as well as recombinant proteins expressed in prokaryotic and eukaryotic systems display high-affinity, specific, displaceable and limited capacity progesterone binding characteristic of steroid membrane receptors. Therefore, membrane progesterone receptors are good candidates for the membrane receptors mediating many of the nonclassical cell surface-initiated progesterone actions, such as oocyte meiotic maturation, granulosa cell apoptosis, immunosuppression of T cells, breast and ovarian cells.[ citation needed ]

It has been found that allopregnanolone, an effective mPR ligand, can act as an mPR agonist at low physiologically relevant concentrations. This indicates an additional receptor mechanism by which neurosteroids can potentially modulate neural functions. [1]

Experimental evidence also supports that mPRs are intermediaries in progestin-induced cell survival. MAP kinase and Akt are involved in inhibition of apoptosis, and it has been demonstrated that progestin activates MAP kinase and Akt through mPRs. This is a fact that consolidates mPR's antiapoptotic functions, and also their potential involvement in the antiapoptotic effects of allopregnanolone in the central nervous system. [1] [21]

MPRs are also considered potential intermediaries in progesterone modulation of GnRH secretion under certain conditions, but direct evidence is lacking.

Structure

As the name says, mPRS are a group of proteins with a receptor function. This determines its location in the cell, the membrane. MPRs recognise some specific substances and facilitate the entrance of these substances inside compartments. Specifically, this receptors allow the entrance to the cell, therefore they are found in the plasmatic membrane. Studies have not revealed significant information about its structure so scientists still do not know exactly how this molecules are. In contrast, studies of the translated cDNAs based on the structure suggest they encode seven transmembrane domains. It also shows that mPRs have high affinity (Kd= 20-30 nm) saturable binding for progesterone – Kd is a constant of every enzyme which says the concentration of ligand needed in order to obtain the half of the saturation. Scientists went further on the study of the binding to the γ-subtype, revealing a specific binding for progesterone with a rate of association and dissociation of t1/2=2–8 minutes. MPRs have a molecular mass of approximately 40 kDa. [20] This results suggest that it may exist a new family of steroid receptors, also with the characteristics of G protein-coupled receptors. Another fact that suggests that this mPR subtype may be a G protein-coupled receptor is that it functions as the intermediary in progesterone induction of the maturation of oocyte meiotic maturation in teleost fishes. [22]

Involvement in cancer

Progesterone takes part in the growth regulation of different kind of tumors, in part by its interactions with its intracellular receptors (PR). MPRs have been found in cancer cells and tissues too. Their roles in the process are unclear but it has been suggested that, at least, this steroid hormone may inhibit tumor progression. Recently, it has been reported that membrane progesterone receptors (mPRs) are expressed in ovarian and breast cancer cells, and that progesterone could exert some actions through these receptors. The presence of functional mPRα, mPRβ, and mPRγ subtypes were detected in both cell lines as well as in breast tumor tissues. [23] [24]

In the case of the ovarian cancer, transcripts for two of the three mPRs, α and β, were differentially expressed in ovarian cystadenomas, borderline tumors, and carcinomas: while mPRα is expressed at significantly higher levels than the others, an increased expression of mPRβ has been noticed in mucinous carcinomas when compared to the other tumor types and normal tissues. Notably, the expression of mPRγ was significantly higher in endometrioid and clear cell carcinomas, which are closely related tumors. [25] In one study, an increase in progesterone was shown to coincide with a reduced level of mPRγ and concomitant increase in the mPRα transcript levels. [26]

Recent studies suggest that some progesterone actions in astrocytoma cells (the most common and malignant human brain tumors) may be mediated also by mPRs. Recently, it has also been discovered that mPRα and mPRβ are clearly expressed at mRNA and protein levels in astrocytoma cells whereas mPRγ was barely expressed in these cells. [27]

See also

Related Research Articles

<span class="mw-page-title-main">Progesterone</span> Sex hormone

Progesterone (P4) is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species. It belongs to a group of steroid hormones called the progestogens and is the major progestogen in the body. Progesterone has a variety of important functions in the body. It is also a crucial metabolic intermediate in the production of other endogenous steroids, including the sex hormones and the corticosteroids, and plays an important role in brain function as a neurosteroid.

<span class="mw-page-title-main">Progestogen</span> Steroid hormone that activates the progesterone receptor

Progestogens, also sometimes written progestagens or gestagens, are a class of natural or synthetic steroid hormones that bind to and activate the progesterone receptors (PR). Progesterone is the major and most important progestogen in the body. The progestogens are named for their function in maintaining pregnancy, although they are also present at other phases of the estrous and menstrual cycles.

<span class="mw-page-title-main">Sex hormone</span> Type of steroid hormone

Sex hormones, also known as sex steroids, gonadocorticoids and gonadal steroids, are steroid hormones that interact with vertebrate steroid hormone receptors. The sex hormones include the androgens, estrogens, and progestogens. Their effects are mediated by slow genomic mechanisms through nuclear receptors as well as by fast nongenomic mechanisms through membrane-associated receptors and signaling cascades. The polypeptide hormones luteinizing hormone, follicle-stimulating hormone and gonadotropin-releasing hormone – each associated with the gonadotropin axis – are usually not regarded as sex hormones, although they play major sex-related roles.

Steroid hormone receptors are found in the nucleus, cytosol, and also on the plasma membrane of target cells. They are generally intracellular receptors and initiate signal transduction for steroid hormones which lead to changes in gene expression over a time period of hours to days. The best studied steroid hormone receptors are members of the nuclear receptor subfamily 3 (NR3) that include receptors for estrogen and 3-ketosteroids. In addition to nuclear receptors, several G protein-coupled receptors and ion channels act as cell surface receptors for certain steroid hormones.

<span class="mw-page-title-main">Progesterone receptor</span> Cytoplasmic receptor protein found inside cells

The progesterone receptor (PR), also known as NR3C3 or nuclear receptor subfamily 3, group C, member 3, is a protein found inside cells. It is activated by the steroid hormone progesterone.

Neurosteroids, also known as neuroactive steroids, are endogenous or exogenous steroids that rapidly alter neuronal excitability through interaction with ligand-gated ion channels and other cell surface receptors. The term neurosteroid was coined by the French physiologist Étienne-Émile Baulieu and refers to steroids synthesized in the brain. The term, neuroactive steroid refers to steroids that can be synthesized in the brain, or are synthesized by an endocrine gland, that then reach the brain through the bloodstream and have effects on brain function. The term neuroactive steroids was first coined in 1992 by Steven Paul and Robert Purdy. In addition to their actions on neuronal membrane receptors, some of these steroids may also exert effects on gene expression via nuclear steroid hormone receptors. Neurosteroids have a wide range of potential clinical applications from sedation to treatment of epilepsy and traumatic brain injury. Ganaxolone, a synthetic analog of the endogenous neurosteroid allopregnanolone, is under investigation for the treatment of epilepsy.

<span class="mw-page-title-main">Selective progesterone receptor modulator</span>

A selective progesterone receptor modulator (SPRM) is an agent that acts on the progesterone receptor (PR), the biological target of progestogens like progesterone. A characteristic that distinguishes such substances from full receptor agonists and full antagonists is that their action differs in different tissues, i.e. agonist in some tissues while antagonist in others. This mixed profile of action leads to stimulation or inhibition in tissue-specific manner, which further raises the possibility of dissociating undesirable adverse effects from the development of synthetic PR-modulator drug candidates.

<span class="mw-page-title-main">CYP17A1</span> Mammalian protein found in Homo sapiens

Cytochrome P450 17A1 is an enzyme of the hydroxylase type that in humans is encoded by the CYP17A1 gene on chromosome 10. It is ubiquitously expressed in many tissues and cell types, including the zona reticularis and zona fasciculata of the adrenal cortex as well as gonadal tissues. It has both 17α-hydroxylase and 17,20-lyase activities, and is a key enzyme in the steroidogenic pathway that produces progestins, mineralocorticoids, glucocorticoids, androgens, and estrogens. More specifically, the enzyme acts upon pregnenolone and progesterone to add a hydroxyl (-OH) group at carbon 17 position (C17) of the steroid D ring, or acts upon 17α-hydroxyprogesterone and 17α-hydroxypregnenolone to split the side-chain off the steroid nucleus.

<span class="mw-page-title-main">Allopregnanolone</span> Endogenous inhibitory neurosteroid

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<span class="mw-page-title-main">GPER</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">LAMP2</span> Protein-coding gene in the species Homo sapiens

Lysosome-associated membrane protein 2 (LAMP2), also known as CD107b and Mac-3, is a human gene. Its protein, LAMP2, is one of the lysosome-associated membrane glycoproteins.

<span class="mw-page-title-main">PGRMC1</span> Protein-coding gene in the species Homo sapiens

Progesterone receptor membrane component 1 is a protein which co-purifies with progesterone binding proteins in the liver and ovary. In humans, the PGRMC1 protein is encoded by the PGRMC1 gene.

<span class="mw-page-title-main">PAQR8</span> Protein-coding gene in the species Homo sapiens

Membrane progesterone receptor beta (mPRβ), or progestin and adipoQ receptor 8 (PAQR8), is a protein that in humans is encoded by the PAQR8 gene.

<span class="mw-page-title-main">5α-Dihydroprogesterone</span> Chemical compound

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<span class="mw-page-title-main">5β-Dihydroprogesterone</span> Chemical compound

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References

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  7. ↑ Thomas P (May 2008). "Characteristics of membrane progestin receptor alpha (mPRalpha) and progesterone membrane receptor component 1 (PGMRC1) and their roles in mediating rapid progestin actions". Frontiers in Neuroendocrinology. 29 (2): 292–312. doi:10.1016/j.yfrne.2008.01.001. PMC   2600886 . PMID   18343488.
  8. ↑ "PAQR8 - Membrane progestin receptor beta - Homo sapiens (Human) - PAQR8 gene & protein". www.uniprot.org. Retrieved 2015-10-30.
  9. ↑ "PAQR8 - Membrane progestin receptor beta - Homo sapiens (Human) - PAQR8 gene & protein". www.uniprot.org. Retrieved 2015-10-27.
  10. ↑ Qiu HB, Lu SS, Ji KL, Song XM, Lu YQ, Zhang M, Lu KH (Dec 2008). "Membrane progestin receptor beta (mPR-beta): a protein related to cumulus expansion that is involved in in vitro maturation of pig cumulus-oocyte complexes". Steroids. 73 (14): 1416–23. doi:10.1016/j.steroids.2008.07.007. PMID   18722396. S2CID   35491199.
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  12. ↑ "PAQR5 - Membrane progestin receptor gamma - Homo sapiens (Human) - PAQR5 gene & protein". www.uniprot.org. Retrieved 2015-10-30.
  13. ↑ Nutu M, Weijdegård B, Thomas P, Bergh C, Thurin-Kjellberg A, Pang Y, Billig H, Larsson DG (Jul 2007). "Membrane progesterone receptor gamma: tissue distribution and expression in ciliated cells in the fallopian tube". Molecular Reproduction and Development. 74 (7): 843–50. doi:10.1002/mrd.20685. PMID   17154304. S2CID   1882789.
  14. ↑ "PAQR6 - Membrane progestin receptor delta - Homo sapiens (Human) - PAQR6 gene & protein". www.uniprot.org. Retrieved 2017-06-15.
  15. ↑ "PAQR9 - Membrane progestin receptor epsilon - Homo sapiens (Human) - PAQR9 gene & protein". www.uniprot.org. Retrieved 2017-06-15.
  16. ↑ "membrane progestin receptor in UniProtKB". www.uniprot.org. Retrieved 2015-10-27.
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  20. 1 2 Singh M, Su C, Ng S (2013-01-01). "Non-genomic mechanisms of progesterone action in the brain". Frontiers in Neuroscience. 7: 159. doi: 10.3389/fnins.2013.00159 . PMC   3776940 . PMID   24065876.
  21. ↑ Song G, Ouyang G, Bao S (2005-03-01). "The activation of Akt/PKB signaling pathway and cell survival". Journal of Cellular and Molecular Medicine. 9 (1): 59–71. doi:10.1111/j.1582-4934.2005.tb00337.x. PMC   6741304 . PMID   15784165.
  22. ↑ Zhu Y, Bond J, Thomas P (Mar 2003). "Identification, classification, and partial characterization of genes in humans and other vertebrates homologous to a fish membrane progestin receptor". Proceedings of the National Academy of Sciences of the United States of America. 100 (5): 2237–42. Bibcode:2003PNAS..100.2237Z. doi: 10.1073/pnas.0436133100 . PMC   151324 . PMID   12601167.
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  26. ↑ Fernandes MS, Pierron V, Michalovich D, Astle S, Thornton S, Peltoketo H, Lam EW, Gellersen B, Huhtaniemi I, Allen J, Brosens JJ (Oct 2005). "Regulated expression of putative membrane progestin receptor homologues in human endometrium and gestational tissues". The Journal of Endocrinology. 187 (1): 89–101. doi: 10.1677/joe.1.06242 . PMID   16214944.
  27. ↑ Valadez-Cosmes P, Germán-Castelán L, González-Arenas A, Velasco-Velázquez MA, Hansberg-Pastor V, Camacho-Arroyo I (Nov 2015). "Expression and hormonal regulation of membrane progesterone receptors in human astrocytoma cells". The Journal of Steroid Biochemistry and Molecular Biology. 154: 176–85. doi:10.1016/j.jsbmb.2015.08.006. PMID   26275946. S2CID   1504553.
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