Progesterone receptor membrane component 1 (PGRMC1) is a 25 kDa protein with an N-terminal transmembrane domain and a putative C-terminal cytochrome b5 domain. Heme-binding activity of PGRMC1 has ...been shown in various homologues of PGRMC1. Although the general definition of PGRMC1 is as a progesterone receptor, progesterone-binding activity has not been directly demonstrated in any of the purified PGRMC1 proteins fully loaded with heme. Here, we show that the human homologue of PGRMC1 (hPGRMC1) binds heme in a five-coordinate (5C) high-spin (HS) configuration, with an axial tyrosinate ligand, likely Y95. The negatively charged tyrosinate ligand leads to a relatively low redox potential of approximately −331 mV. The Y95C or Y95F mutation dramatically reduces the ability of the protein to bind heme, supporting the assignment of the axial heme ligand to Y95. On the other hand, the Y95H mutation retains ∼90% of the heme-binding activity. The heme in Y95H is also 5CHS, but it has a hydroxide axial ligand, conceivably stabilized by the engineered-in H95 via an H-bond; CO binding to the distal ligand-binding site leads to an exchange of the axial ligand to a histidine, possibly H95. We show that progesterone binds to hPGRMC1 and introduces spectral changes that manifest conformational changes to the heme. Our data offer the first direct evidence supporting progesterone-binding activity of PGRMC1.
The steroid hormone progesterone (P₄) plays a key role in the reproductive events associated with pregnancy establishment and maintenance. High concentrations of circulating P₄ in the immediate ...post-conception period have been associated with an advancement of conceptus elongation, an associated increase in interferon-τ production and higher pregnancy rates in cattle. Using in vitro and in vivo models and ~8500 bovine oocytes across six experiments, the aim of this study was to establish the route through which P₄ affects bovine embryo development in vitro and in vivo. mRNA for P₄ receptors was present at all stages of embryo development raising the possibility of a direct effect of P₄ on the embryo. Exposure to P₄ in vitro in the absence or presence of oviduct epithelial cells did not affect the proportion of embryos developing to the blastocyst stage, blastocyst cell number or the relative abundance of selected transcripts in the blastocyst. Furthermore, exposure to P₄ in vitro did not affect post-hatching elongation of the embryo following transfer to synchronized recipients and recovery on Day 14. By contrast, transfer of in vitro derived blastocysts to a uterine environment previously primed by elevated P₄ resulted in a fourfold increase in conceptus length on Day 14. These data provide clear evidence to support the hypothesis that P₄-induced changes in the uterine environment are responsible for the advancement in conceptus elongation reported previously in cattle and that, interestingly, the embryo does not need to be present during the period of high P₄ in order to exhibit advanced elongation.
•Progesterone regulation of neuronal activity and seizures.•Progesterone receptor activation exerts seizure-promoting effects.•Progesterone receptor activation could contribute to catamenial seizure ...exacerbation.•Allopregnanolone suppresses seizure activity through potentiation of GABAA receptors.
Progesterone acts on neurons directly by activating its receptor and through metabolic conversion to neurosteroids. There is emerging evidence that progesterone exerts excitatory effects by activating its cognate receptors (progesterone receptors, PRs) through enhanced expression of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs). Progesterone metabolite 5α,3α-tetrahydro-progesterone (allopregnanolone, THP) mediates its anxiolytic and sedative actions through the potentiation of synaptic and extrasynaptic γ-aminobutyric acid type-A receptors (GABAARs). Here, we review progesterone's neuromodulatory actions exerted through PRs and THP and their opposing role in regulating seizures, catamenial epilepsy, and seizure exacerbation associated with progesterone withdrawal.
Endometriosis is an estrogen-dependent disease characterized by the growth of endometrial-like tissue outside the uterus. Progestins are currently the most commonly used treatment for endometriosis ...because of their excellent therapeutic effects and limited side effects. However, progestins have been unsuccessful in some symptomatic patients. The inability of the endometrium to respond properly to progesterone is known as progesterone resistance. An increasing body of evidence suggests the loss of progesterone signaling and the existence of progesterone resistance in endometriosis. The mechanisms of progesterone resistance have received considerable scholarly attention in recent years. Abnormal PGR signaling, chronic inflammation, aberrant gene expression, epigenetic alterations, and environmental toxins are considered potential molecular causes of progesterone resistance in endometriosis. The general objective of this review was to summarize the evidence and mechanisms of progesterone resistance. A deeper understanding of how these mechanisms contribute to progesterone resistance may help develop a novel therapeutic regimen for women with endometriosis by reversing progesterone resistance.
Abstract
Ovarian cancer (OC) represents a collection of rare but lethal gynecologic cancers where the difficulty of early detection due to an often-subtle range of abdominal symptoms contributes to ...high fatality rates. With the exception of BRCA1/2 mutation carriers, OC most often manifests as a post-menopausal disease, a time in which the ovaries regress and circulating reproductive hormones diminish. Progesterone is thought to be a “protective” hormone that counters the proliferative actions of estrogen, as can be observed in the uterus or breast. Like other steroid hormone receptor family members, the transcriptional activity of the nuclear progesterone receptor (nPR) may be ligand dependent or independent and is fully integrated with other ubiquitous cell signaling pathways often altered in cancers. Emerging evidence in OC models challenges the singular protective role of progesterone/nPR. Herein, we integrate the historical perspective of progesterone on OC development and progression with exciting new research findings and critical interpretations to help paint a broader picture of the role of progesterone and nPR signaling in OC. We hope to alleviate some of the controversy around the role of progesterone and give insight into the importance of nPR actions in disease progression. A new perspective on the role of progesterone and nPR signaling integration will raise awareness to the complexity of nPRs and nPR-driven gene regulation in OC, help to reveal novel biomarkers, and lend critical knowledge for the development of better therapeutic strategies.
Graphical Abstract
Graphical Abstract
Several receptors for nongenomically initiated actions of progesterone (P4) exist, namely membrane-associated P4 receptors (MAPRs), membrane progestin receptors (mPRs), receptors for neurosteroids ...GABAA receptor (GABAAR), NMDA receptor, sigma-1 and -2 receptors (S1R/S2R), the classical genomic P4 receptor (PGR), and α/β hydrolase domain-containing protein 2 (ABHD2). Two drugs related to this field have been approved: brexanolone (Zulresso™) for the treatment of postpartum depression, and ganaxolone (Ztalmy™) for the treatment of CDKL5 deficiency disorder. Both are derivatives of P4 and target the GABAAR. Several other indications are in clinical testing. CT1812 (Elayta™) is also being tested for the treatment of Alzheimer’s disease (AD) in Phase 2 clinical trials, targeting the P4 receptor membrane component 1 (PGRMC1)/S2R complex. In this Review, we highlight emerging knowledge on the mechanisms of nongenomically initiated actions of P4 and its derivatives.
The progesterone (P4) receptor membrane component 1 (PGRMC1)/sigma-2 receptor (S2R) complex may be of clinical significance in the treatment of Alzheimer’s disease. It is targeted by a small molecule (Elayta™), which is being tested in clinical trials. Furthermore, PGRMC1 shows promising preclinical results in several other indications, including the diagnosis and treatment of cancer.Membrane progestin receptors have also been shown to be involved in a multitude of different physiological functions. Information on the critical residues required for P4 binding to the receptor is available, although a translational outcome is still lacking.In the field of neurosteroids, brexanolone (Zulresso™) and ganaxolone (Ztalmy™) have been approved for the treatment of postpartum depression and CDKL5 deficiency disorder, respectively. Several other indications are being tested clinically.α/β Hydrolase domain-containing protein 2 (ABHD2) has been identified as a new P4 receptor; in addition to its role in the activation of CatSper, it also appears to be involved in several other nongenomic P4 actions.
Progesterone Receptor Signaling Mechanisms Grimm, Sandra L.; Hartig, Sean M.; Edwards, Dean P.
Journal of molecular biology,
09/2016, Letnik:
428, Številka:
19
Journal Article
Recenzirano
Progesterone receptor (PR) is a master regulator in female reproductive tissues that controls developmental processes and proliferation and differentiation during the reproductive cycle and ...pregnancy. PR also plays a role in progression of endocrine-dependent breast cancer. As a member of the nuclear receptor family of ligand-dependent transcription factors, the main action of PR is to regulate networks of target gene expression in response to binding its cognate steroid hormone, progesterone. This paper summarizes recent advances in understanding the structure–function properties of the receptor protein and the tissue/cell-type-specific PR signaling pathways that contribute to the biological actions of progesterone in the normal breast and in breast cancer.
Dynamic structures of the steroid hormone receptor (SHR). The conformational flexibility of SHR is mediated by the intrinsically disordered amino-terminal domain (NTD) and by allosteric interactions between domains ligand-binding domain (LBD) and DNA-binding domain (DBD). The apo SHR (left side of diagram) in response to binding co-regulatory proteins (CoRs), DNA, and steroidal ligands undergoes conformational changes to a transcriptionally active receptor (right side of diagram). Changes include folding and stabilization of the NTD, allosteric interdomain interactions, and repositioning of helix 12 in the LBD, enabling the binding of CoRs containing LXXLL motifs. Shadows around LBD and DBD are potential avenues of interdomain interactions. Binding proteins that induce folding and stabilization of NTD may function directly as a CoR or by reorganizing structure of the NTD enabling binding of other CoRs. Display omitted
•PR mediates variable responses to progesterone in a context-dependent manner.•Conformational flexibility of PR structure contributes to functional diversity.•Unique signaling mechanisms contribute to cell-specific actions of progesterone.•New tools are needed to advance structure studies of intact PR–protein complexes.•New models are advancing the understanding of the role of PR in breast cancer progression.
The precise timing of progesterone signaling through its cognate receptor, the progesterone receptor (PGR), is critical for the establishment and maintenance of pregnancy. Loss of PGR expression in ...the murine uterine epithelium during the preimplantation period is a marker for uterine receptivity and embryo attachment. We hypothesized that the decrease in progesterone receptor A (PGRA) expression is necessary for successful embryo implantation. To test this hypothesis, a mouse model constitutively expressing PGRA (mPgrALsL/+) was generated. Expression of PGRA in all uterine compartments (Pgrcre) or uterine epithelium (Wnt7acre) resulted in infertility with defects in embryo attachment and stromal decidualization. Expression of critical PGRA target genes, indian hedgehog, and amphiregulin (Areg), wasmaintained through the window of receptivity while the estrogen receptor target gene, the leukemia inhibitory factor (Lif), a key regulator of embryo receptivity, was decreased. Transcriptomic and cistromic analyses of the mouse uterus at day 4.5 of pregnancy identified an altered group of genes regulating molecular transport in the control of fluid and ion levels within the uterine interstitial space. Additionally, LIF and its cognate receptor, the leukemia inhibitory factor receptor (LIFR), exhibited PGR-binding events in regions upstream of the transcriptional start sites, suggesting PGRA is inhibiting transcription at these loci. Therefore, downregulation of the PGRA isoform at the window of receptivity is necessary for the attenuation of hedgehog signaling, transcriptional activation of LIF signaling, and modulation of solutes and fluid, producing a receptive environment for the attaching embryo. Summary Sentence Expression of PGRA at the window of receptivity transcriptionally represses LIF signaling and aberrantly regulates hedgehog and solute signaling rendering the uterus unreceptive to the implanting embryo.
► Progesterone receptor (PR) levels are regulated by estrogen-dependent and independent pathways. ► PR mediated gene regulation as studied by expression profiling. ► Prevalence of PRE half-sites ...suggests that PR monomers and dimers can regulate transcription. ► PR, transcription factor cooperativity, and role of co-response elements. ► The PR isoforms, PR-A and PR-B, regulate overlapping and distinct gene subsets.
This review discusses mechanisms by which progesterone receptors (PR) regulate transcription. We examine available data in different species and tissues regarding: (1) regulation of PR levels; and (2) expression profiling of progestin-regulated genes by total PRs, or their PRA and PRB isoforms. (3) We address current views about the composition of progesterone response elements, and postulate that PR monomers acting through “half-site” elements are common, entailing cooperativity with neighboring DNA-bound transcription factors. (4) We summarize transcription data for multiple progestin-regulated promoters as directed by total PR, or PRA vs. PRB. We conclude that current models and methods used to study PR function are problematical, and recommend that future work employ cells and receptors appropriate to the species, focusing on analyses of the effects of endogenous receptors targeting endogenous genes in native chromatin.
Abstract Rapid, progestin actions initiated at the cell surface that are often nongenomic have been described in a variety of reproductive tissues, but until recently the identities of the membrane ...receptors mediating these nonclassical progestins actions remained unclear. Evidence has been obtained in the last 4–5 years for the involvement of two types of novel membrane proteins unrelated to nuclear steroid receptors, progesterone membrane receptors (mPRs) and progesterone receptor membrane component 1 (PGMRC1), in progestin signaling in several vertebrate reproductive tissues and in the brain. The mPRs, ( MW ∼40 kDa) initially discovered in fish ovaries, comprise at least three subtypes, α, β and γ and belong to the seven-transmembrane progesterone adiponectin Q receptor (PAQR) family. Both recombinant and wildtype mPRs display high affinity ( Kd ∼5 nM), limited capacity, displaceable and specific progesterone binding. The mPRs are directly coupled to G proteins and typically activate pertussis-sensitive inhibitory G proteins (Gi ), to down-regulate adenylyl cyclase activity. Recent studies suggest the alpha subtype (mPRα) has important physiological functions in variety of reproductive tissues. The mPRα is an intermediary in progestin induction of oocyte maturation and stimulation of sperm hypermotility in fish. In mammals, the mPRαs have been implicated in progesterone regulation of uterine function in humans and GnRH secretion in rodents. The single-transmembrane protein PGMRC1 ( MW 26–28 kDa) was first purified from porcine livers and its cDNA was subsequently cloned from porcine smooth muscle cells and a variety of other tissues by different investigators. PGMRC1 and the closely-related PGMRC2 belong to the membrane-associated progesterone receptor (MAPR) family. The PGMRC1 protein displays moderately high binding affinity for progesterone which is 2- to 10-fold greater than that for testosterone and glucocorticoids, and also can bind to other molecules such as heme, cholesterol metabolites and proteins. The signal transduction pathways induced by binding of progesterone to PGMRC1 have not been described to date, although motifs for tyrosine kinase, kinase binding, SH2 and SH3 have been predicted from the amino acid sequence. Evidence has been obtained that PGMRC1 mediates the antiapoptotic affects of progesterone in rat granulosa cells. The PGMRC1 protein may also be an intermediary in the progesterone induction of the acrosome reaction in mammalian sperm. Despite these recent advances, many aspects of progestin signaling through these two families of novel membrane proteins remain unresolved. Biochemical characterization of the receptors has been hampered by rapid degradation of the partially purified proteins. A major technical challenge has been to express sufficient amounts of the recombinant receptors on the plasma membranes in eukaryotic systems to permit investigations of their progestin binding and signal transduction characteristics. Additional basic information on the molecular and cellular mechanisms by which mPRs and PGMRC1 interact with progestins, signal transductions pathways and other proteins will be required to establish a comprehensive model of nontraditional progestin actions mediated through these novel proteins.
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