A membrane-associated progesterone-binding protein, 25-Dx, is regulated by progesterone in brain regions involved in female reproductive behaviors

Abstract

The ventromedial hypothalamus (VMH) plays a central role in the regulation of the female reproductive behavior lordosis, a behavior dependent upon the sequential activation of receptors for the ovarian steroid hormones estradiol (E) and progesterone (P). These receptors function as transcription factors to alter the expression of target genes. To discover behaviorally relevant genes targeted by E and P in the VMH, we used the differential display PCR to identify messenger RNAs that are differentially expressed in the hypothalamus of ovariectomized (ovx) rats treated with E alone compared with ovariectomized rats treated with E and P. We show here that one interesting mRNA within the hypothalamus that is repressed by P after E priming encodes the protein 25-Dx, the rat homolog of the human membrane-associated P-binding protein Hpr6.6. Neurons in the brain containing the highest levels of 25-Dx are located in several nuclei of the basal forebrain, including the VMH. 25-Dx expression is also higher in the hypothalamus of female P receptor ''knockout'' mice than in their wild-type littermates. These findings suggest a mechanism in which the activation of nuclear P receptor represses expression of a membrane P receptor, 25-Dx, during lordosis facilitation. L ordosis is a reproductive behavior, characterized by the rigid dorsiflexion of the spinal column and elevation of the hind quarters observed in mating female rodents. The lordosis posture allows intromission by the male and is due to elevated circulating levels of estradiol (E) and progesterone (P) from the ovaries, which occurs during proestrus, accompanied by gentle pressure on the vagina from the male (1). Lordosis is also observed in ovariectomized (ovx) females given exogenous hormone followed by gentle pressure on the perineum (1). This model system underscores the behavior's dependence on E, P, and tactile stimulation (2) and is widely used to examine the influence of E, P, and somatosensory effects on an easily identifiable reproductive behavior.By tracing the somatosensory input, Pfaff et al. (2) have constructed a detailed map of the neural circuitry responsible for lordosis. One brain structure important for integrating the endocrine aspect with other neural events surrounding lordosis is the ventromedial hypothalamus (VMH) (2). The VMH contains an abundance of E and P receptors (2), ligand-activated transcription factors (3) that act within the nuclei of VMH neurons. Under a lordosis-producing hormone regimen, E, operating through the transcriptional activity of the activated estrogen receptor, has been shown to increase the transcription of oxytocin and the oxytocin receptor, gonadotropin-releasing hormone and the gonadotropin-releasing hormone receptor, preproenkephalin (PPE), the opioid receptor, and the progesterone receptor (PR) (4). The transcriptional targets of activated PR within this brain region have been more difficult to ascertain, but recent work has identified a few P-responsive genes in the brain that may reside within the lordosis pat...

Involvement of let-7/miR-98 microRNAs in the regulation of progesterone receptor membrane component 1 expression in ovarian cancer cells

“…Additionally, these results show that the prediction of miRNA binding sites in a certain target by software programs definitely must be confirmed by experimental approaches. Finally, our in vitro studies support previous studies, which show that P4 regulates PGRMC1 mRNA levels (7,13,14,33). However, the effect of P4 on PGRMC1 expression seems to be tissue specific, since a downregulation of PGRMC1 by P4 was detected in some tissues, while an upregulation was shown in others (7).…”

“…PGRMC1 mRNA levels are regulated by P4 in several tissues (13,14). In order to analyze the effect of P4 on PGRMC1 expression in SKOV-3 cells, cells were incubated with 0 or 1000 nM P4 for 24 h. Treatment of SKOV-3 cells with 1000 nM P4 suppressed native PGRMC1 mRNA levels by ~20% of control values (P<0.05; Fig.…”

“…Therefore, this study was designed to investigate the functional importance of these sites in regulating PGRMC1 expression. Additionally, the Involvement of let-7/miR-98 microRNAs in the regulation of progesterone receptor membrane component 1 expression in ovarian cancer cells influence of progesterone (P4) on miRNAs regulating PGRMC1 was analyzed, since progesterone (P4) regulates PGRMC1 expression in a tissue-dependent manner (13,14), which may involve miRNAs.…”

Measurement of the Heme Affinity for Yeast Dap1p, and Its Importance in Cellular Function

“…Reports of progesterone binding are predominantly with the porcine homologue PGRMC1, which was measured to have two binding affinities to progesterone, 11 nM and 286 nM (1). There is additional evidence for regulation of rat PGRMC1 (also known as Vema, IZA, 25-Dx, and sometimes mPR) by progesterone and involvement of PGRMC1 in cellular, non-genomic progesterone responses (37)(38)(39)(40)(41)(42). However, progesterone binding by rat PGRMC1, was later shown to be nonspecific and weak by Min et al (5).…”

Neurosteroid regulation of central nervous system development

“…These effects are likely to be mediated through progesterone's action on the nuclear progesterone receptor, since the antiprogestin RU-486 blocks these effects, and the progesterone metabolite allopregnanolone does not affect these parameters of Purkinje cell development. The membrane 25-Dx progesterone receptor, which is a putative membrane progesterone receptor (Gerdes et al, 1998;Krebs et al, 2000), may also mediate some of these effects (Sakamoto et al, 2004). This receptor is now referred to as progesterone membrane receptor component 1 (PGRMC1) (Crudden et al, 2006;Engmann et al, 2006;Peluso et al, 2006;Viero et al, 2006).…”