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.
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).
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]
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.
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.
Membrane progesterone receptor delta (mPRδ) is a protein that in humans is encoded by the PAQR6 gene. [14]
Membrane progesterone receptor epsilon (mPRϵ) is a protein that in humans is encoded by the PAQR9 gene. [15]
Family members include: [16]
mPR subtype | Gene | Length | Mass (Da) | Tissue specificity |
---|---|---|---|---|
mPRα | PAQR7 | 346 | 39,719 | Ovary, testis, placenta, uterus, bladder, others [17] |
mPRβ | PAQR8 | 354 | 40,464 | Brain, spinal cord, kidney, testis, others [17] |
mPRγ | PAQR5 | 330 | 38,014 | Brain, lung, kidney, colon, adrenal, others [17] |
mPRδ | PAQR6 | 344 | 37,989 | Brain, breast, others [17] [18] |
mPRϵ | PAQR9 | 377 | 42,692 | Brain, 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.
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.
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]
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]
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.
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.
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.
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.
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.
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.
Allopregnanolone is a naturally occurring neurosteroid which is made in the body from the hormone progesterone. As a medication, allopregnanolone is referred to as brexanolone, sold under the brand name Zulresso, and used to treat postpartum depression. It is given by injection into a vein.
G protein-coupled estrogen receptor 1 (GPER), also known as G protein-coupled receptor 30 (GPR30), is a protein that in humans is encoded by the GPER gene. GPER binds to and is activated by the female sex hormone estradiol and is responsible for some of the rapid effects that estradiol has on cells.
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.
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.
Membrane progesterone receptor beta (mPRβ), or progestin and adipoQ receptor 8 (PAQR8), is a protein that in humans is encoded by the PAQR8 gene.
5α-Dihydroprogesterone is an endogenous progestogen and neurosteroid that is synthesized from progesterone. It is also an intermediate in the synthesis of allopregnanolone and isopregnanolone from progesterone.
Membrane steroid receptors (mSRs), also called extranuclear steroid receptors, are a class of cell surface receptors activated by endogenous steroids that mediate rapid, non-genomic signaling via modulation of intracellular signaling cascades. mSRs are another means besides classical nuclear steroid hormone receptors (SHRs) for steroids to mediate their biological effects. SHRs can produce slow genomic responses or rapid, non-genomic responses in the case of mSRs.
5β-Dihydroprogesterone is an endogenous neurosteroid and an intermediate in the biosynthesis of pregnanolone and epipregnanolone from progesterone. It is synthesized from progesterone by the enzyme 5β-reductase.
Eps15 homology domain-containing protein 3, abbreviated as EHD3 and also known as PAST3, is a protein encoded by the EHD3 gene. It has been observed in humans, mice and rats. It belongs to the EHD protein family, a group of four membrane remodeling proteins related to the Dynamin superfamily of large GTPases. Although the four of them are 70-80% amino acid identical, they all have different locations. Its main function is related to endocytic transport.
Chromosome 19 open reading frame 18 (c19orf18) is a protein which in humans is encoded by the c19orf18 gene. The gene is exclusive to mammals and the protein is predicted to have a transmembrane domain and a coiled coil stretch. This protein has a function that is not yet fully understood by the scientific community.
The pharmacology of progesterone, a progestogen medication and naturally occurring steroid hormone, concerns its pharmacodynamics, pharmacokinetics, and various routes of administration.
Transmembrane protein 248, also known as C7orf42, is a gene that in humans encodes the TMEM248 protein. This gene contains multiple transmembrane domains and is composed of seven exons.TMEM248 is predicted to be a component of the plasma membrane and be involved in vesicular trafficking. It has low tissue specificity, meaning it is ubiquitously expressed in tissues throughout the human body. Orthology analyses determined that TMEM248 is highly conserved, having homology with vertebrates and invertebrates. TMEM248 may play a role in cancer development. It was shown to be more highly expressed in cases of colon, breast, lung, ovarian, brain, and renal cancers.