Biochemical and Biophysical Research Communications
Regular ArticleFull-Length cDNA Sequence of a Progesterone Membrane-Binding Protein from Porcine Vascular Smooth Muscle Cells☆
Abstract
A full-length cDNA clone for a progesterone membrane binding protein from porcine vascular smooth muscle cells was isolated and the complete nucleotide sequence determined. The cDNA encodes a protein of 194 amino acids with a transmembrane segment. This protein is likely to represent the first steroid membrane receptor or a part of it for which sequence information is available.
References (0)
Cited by (189)
Changes in the conflicting nongenomic effects of progesterone in rat myometrium during pregnancy
2024, Life SciencesAlthough the functions of progesterone in the myometrium are well-established, the nongenomic effects of progesterone in pregnant myometrial contractions are still unclear. Therefore, this study aimed to investigate changes in the nongenomic effects of progesterone during pregnancy.
Myometrial strips were obtained from non-pregnant, pregnant, and postpartum rats, and the nongenomic effects of progesterone in the myometrium during pregnancy were examined. Additionally, the influence of actinomycin D and cycloheximide and the effects of Org OD-02-0 (a specific membrane progesterone receptor (mPR) agonist) in the myometrium were investigated. Moreover, DNA microarray and quantitative real-time polymerase chain reaction (qRT-PCR) were performed to identify genes involved in progesterone-induced effects in the myometrium.
Progesterone did not cause rhythmic contractions in non-pregnant myometrium but induced rhythmic contractions in pregnant myometrium, with the effects peaking at 20 d + 8 h of pregnancy. However, myometrial contractions decreased after delivery and were restored to non-pregnant levels at 7 d postpartum. Additionally, progesterone stably inhibited high KCl-induced myometrial contractions during pregnancy. Moreover, the nongenomic effects of progesterone were unaffected by actinomycin D or cycloheximide, and Org OD-02-0 effectively mimicked these effects. DNA microarray analysis and qRT-PCR revealed a significant increase in mPRβ gene expression during pregnancy. However, mPRα, mPRγ, mPRδ, and mPRε expression levels remained unchanged.
The stimulatory nongenomic effect of progesterone, which was inducible and mPRβ-dependent during pregnancy, may be involved in parturition. The inhibitory effect, which was constitutive and depended on other mPRs, may be involved in pregnancy maintenance.
Dynamic expression of PGRMC1 and SERBP1 in human endometrium: an implication in the human decidualization process
2017, Fertility and SterilityTo characterize PGRMC1 and SERBP1 in human endometrium and to investigate the putative role of PGRMC1 in endometrial decidualization.
The PGRMC1 and SERBP1 expression in human endometrium was determined throughout the menstrual cycle. We analyzed the colocalization of PGRMC1 and SERBP1. Then, endometrial stromal cells (ESCs) were isolated to investigate the functional effect of PGRMC1 overexpression on decidualization.
IVI clinic.
Endometrial biopsies were collected from fertile volunteers (n = 61) attending the clinic as ovum donors.
Endometrial samples of 61 healthy fertile women.
In vivo localization of PGRMC1 and SERBP1 was assessed by immunohistochemistry. The PGRMC1/SERBP1 colocalization was investigated in vitro and in vivo. Decidualization effect of PGRMC1 overexpression was evaluated in primary ESC cultures.
The PGRMC1 was detected in the endometrial stroma throughout the menstrual cycle, but decreased in the late secretory phase. The SERBP1 immunostaining was present in stroma and increased in the entire the menstrual cycle. The PGRMC1 and SERBP1 colocalized in the cytoplasmic fractions of nondecidualized and decidualized ESC. The PGRMC1 overexpression significantly inhibited in vitro decidualization.
Our results suggest that classic P receptors (PRs) are not the only kind playing a role in the normal physiology of the endometrium. The human decidualization process could be altered by the overexpression or mislocalization of PGRMC1 in ESC.
Potential applications for sigma receptor ligands in cancer diagnosis and therapy
2015, Biochimica et Biophysica Acta - BiomembranesCitation Excerpt :But the important study of Xu et al. [13] provided actual proof for the identity of the sigma-2 receptor and PGRMC1. Since PGRMC1 is a known protein, the cDNA sequence of the sigma-2 receptor gene may in fact already have been determined, both in porcine [15] and human [16] tissues. Although the close identity of the sigma-2 receptor and PGRMC1 appears to have been established, some questions remain unanswered.
Sigma receptors (sigma-1 and sigma-2) represent two independent classes of proteins. Their endogenous ligands may include the hallucinogen N,N-dimethyltryptamine (DMT) and sphingolipid-derived amines which interact with sigma-1 receptors, besides steroid hormones (e.g., progesterone) which bind to both sigma receptor subpopulations. The sigma-1 receptor is a ligand-regulated molecular chaperone with various ion channels and G-protein-coupled membrane receptors as clients. The sigma-2 receptor was identified as the progesterone receptor membrane component 1 (PGRMC1). Although sigma receptors are over-expressed in tumors and up-regulated in rapidly dividing normal tissue, their ligands induce significant cell death only in tumor tissue. Sigma ligands may therefore be used to selectively eradicate tumors. Multiple mechanisms appear to underlie cell killing after administration of sigma ligands, and the signaling pathways are dependent both on the type of ligand and the type of tumor cell. Recent evidence suggests that the sigma-2 receptor is a potential tumor and serum biomarker for human lung cancer and an important target for inhibiting tumor invasion and cancer progression. Current radiochemical efforts are focused on the development of subtype-selective radioligands for positron emission tomography (PET) imaging. Right now, the mostpromising tracers are [18F]fluspidine and [18F]FTC-146 for sigma-1 receptors and [11C]RHM-1 and [18F]ISO-1 for the sigma-2 subtype. Nanoparticles coupled to sigma ligands have shown considerable potential for targeted delivery of antitumor drugs in animal models of cancer, but clinical studies exploring this strategy in cancer patients have not yet been reported. This article is part of a Special Issue entitled: Membrane channels and transporters in cancers.
Evidence that progestins play an important role in spermiation and pheromone production in male sea lamprey (Petromyzon marinus)
2015, General and Comparative EndocrinologyProgestins (progestogens, C21 steroids) have been shown to regulate key physiological activities for reproduction in both sexes in all classes of vertebrates except for Agnathans. Progesterone (P) and 15α-hydroxyprogesterone (15α-P) have been detected in sea lamprey (Petromyzon marinus) plasma, but the expression patterns and functions of putative progestin receptor genes have not yet been investigated. The first objective of this study was to determine the differences in mRNA expression levels of nuclear progestin receptor (nPR) and the membrane receptor adaptor protein ‘progesterone receptor membrane component 1’ (pgrmc1) in putative target tissues in males at different life stages, with and without lamprey GnRH-I and -III treatment. The second objective was to demonstrate the function of progestins by implanting prespermiating males (PSM) with time-release pellets of P and measuring the latency to the onset of spermiation and plasma concentrations of sex pheromones and steroids. The third objective was to measure the binding affinity of P in the nuclear and membrane fractions of the target tissues. Expression levels of nPR and pgrmc1 differed between life stages and tissues, and in some cases were differentially responsive to lamprey GnRH-I and -III. Increases in nPR and pgrmc1 gene expressions were correlated to the late stages of sexual maturation in males. The highest expression levels of these genes were found in the liver and gill of spermiating males. These organs are, respectively, the site of production and release of the sex pheromone 3 keto-petromyzonol sulfate (3kPZS). The hypothesis that pheromone production may be under hormonal control was tested in vivo by implanting PSM with time-release pellets of P. Concentrations of 3kPZS in plasma after 1 week were 50-fold higher than in controls or in males that had been implanted with androstenedione, supporting the hypothesis that P is responsible for regulating the production of the sex pheromone. P treatment also accelerated the onset of spermiation. Saturation and Scatchard analyses of the target tissues showed that both nuclear and membrane fractions bound P with high affinity and low capacity (KD 0.53 pmol/g testis and 0.22 pmol/g testis, and Bmax 1.8 and 5.7 nM, respectively), similar to the characteristics of nPR and mPR in other fish. The fact that a high proportion of P was also converted in vivo to 15α-P means that it is not yet possible to determine which of these two steroids is the natural ligand in the sea lamprey.
Pyridine analogues of spirocyclic σ<inf>1</inf> receptor ligands
2014, Bioorganic and Medicinal ChemistrySpirocyclic benzopyrans 2 interact with high affinity and selectivity with σ1 receptors. Bioisosteric replacement of the benzene ring of the benzopyran substructure with the electron rich thiophene ring (3) led to increased σ1 affinity. Herein the synthesis and pharmacological evaluation of electron deficient pyridine bioisosteres 4 are reported. Homologation of the aldehyde 6 to afford the pyridylacetaldehyde derivative 8 was performed by a Wittig reaction. Bromine lithium exchange of the bromopyridine 8, addition to 1-benzylpiperidin-4-one and cyclization led to the spirocyclic pyrranopyridine 10. Hydrogenolytic removal of the N-benzyl moiety of 10 provided the secondary amine 11, which allowed the introduction of various N-substituents (12a–d). Cyclization of the hydroxy acetal 9 with HCl led to various modifications of the substituent in 3′-position. Generally the σ1 affinity of the pyridine derivatives is reduced compared with those of the benzene and thiophene derivatives 2 and 3. However, the relationships between the structure and the σ1 affinity follow the same rules as for the benzene and thiophene derivatives. The most promising σ1 ligand within this class of compounds is the pyranopyridine 15 with a double bond in the pyran ring revealing a Ki-value of 4.6 nM and a very high selectivity (>217-fold) over the σ2 subtype.
Hypertensive disorders of pregnancy and gestational diabetes mellitus among French Caribbean women chronically exposed to chlordecone
2014, Environment InternationalFew studies have explored the consequences of environmental exposure to organochlorine pesticides for gestational hypertension (GH), preeclampsia (PE) and gestational diabetes mellitus (GDM). Chlordecone is a persistent organochlorine pesticide that was used intensively, and almost exclusively, in the French West Indies until 1993. We investigated the impact of prenatal exposure to chlordecone on the occurrence of GDM, GH and PE by studying 779 pregnant women enrolled in a prospective mother–child cohort (Timoun Study) in Guadeloupe between 2004 and 2007. Chlordecone exposure was determined by assaying maternal plasma and information about pregnancy complications was obtained from midwives, pediatricians and hospital medical records after delivery. The risks of GH (n = 65), PE (n = 31) and GDM (n = 71) were estimated by multiple logistic regression including potential confounders. Levels of chlordecone plasma concentration in the third (OR = 0.2; 95% confidence interval (CI): 0.1, 0.5) and fourth quartiles (OR = 0.3; 95% CI: 0.2, 0.7) were associated with a statistically significant decrease in the risk of GH. A log10 increase in chlordecone concentration was significantly associated with lower risk of GH (OR = 0.4; 95% CI: 0.2, 0.6). No significant associations were observed between the chlordecone exposure and the risk of PE or GDM. This study suggests an inverse association between chlordecone exposure during pregnancy and GH. Further studies are required to determine the underlying mechanism, or the potential unknown confounding factors, resulting in this association.
- ☆
The sequence data reported in this paper have the accession number X99714 in the EMBL Data Library.
- 1
To whom correspondence should be addressed. Fax: 0049 0621/383 2024.