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Pituitary adenylate cyclase‐activating peptide (PACAP) receptor (PAC1R) is a class B Gprotein‐coupled receptor (GPCR) that is widely expressed in the human body and is involved in neuronal differentiation. As class B GPCRs are known to form heterocomplexes with family members, we hypothesized that PAC1R mediates neuronal differentiation through interaction with a class B GPCR. We used the BRET assay to identify potential interactions between PAC1R and 11 class B GPCRs. Gastric inhibitory polypeptide receptor (GIPR) and secretin receptor were identified as putative binding partners of PAC1R. The effect of heterocomplex formation by PAC1R on receptor activation was evaluated with the cyclic (c)AMP, luciferase reporter, and calcium signaling assays; and the effects on receptor internalization and subcellular localization were examined by confocal microscopy. The results suggested he PAC1R/GIPR heterocomplex suppressed signaling events downstream of PAC1R, including cAMP production, serum response element and calcium signaling, and β‐arrestin recruitment. Protein–protein interaction was analyzed in silico, and induction of neuronal differentiation by the PAC1R heterocomplex was assessed in SH‐SY5Y neuronal cells by measure the morphological changes and marker genes expression by real‐time quantitative PCR and western blot. Over‐expression of GIPR suppressed PACAP/PAC1R‐mediated neuronal differentiation and the differentiation markers expression in SH‐SY5Y cells. GIPR regulates neuronal differentiation through heterocomplex formation with PAC1R. [ABSTRACT FROM AUTHOR]

Secretin (SCT) and its receptor (SCTR) are important in fluid regulation at multiple levels via the modulation of expression and translocation of renal aquaporin 2 and functions of central angiotensin II (ANGII). The functional interaction of SCT with peripheral ANGII, however, remains unknown. As the ANGII-aldosterone axis dominates the regulation of renal epithelial sodium channel (ENaC) function, we therefore tested whether SCT/SCTR can regulate sodium homeostasis via the renin-angiotensin-aldosterone system. SCTR-knockout (SCTR-/-) mice showed impaired aldosterone synthase (CYP11B2) expression and, consequently, aldosterone release upon intraperitoneal injection of ANGII. Endogenous ANGII production induced by dietary sodium restriction was higher in SCTR-/- than in C57BL/6N [wild-type (WT)] mice, but CYP11B2 and aldosterone synthesis were not elevated. Reduced accumulation of cholesteryl ester--the precursor of aldosterone--was observed in adrenal glands of SCTR-/- mice that were fed a low-sodium diet. Absence of SCTR resulted in elevated basal transcript levels of adrenal CYP11B2 and renal ENaCs. Although transcript and protein levels of ENaCs were similar in WT and SCTR-/- mice under sodium restriction, ENaCs in SCTR-/- mice were less sensitive to amiloride hydrochloride. In summary, the SCT/SCTR axis is involved in aldosterone precursor uptake, and the knockout of SCTR results in defective aldosterone biosynthesis/release and altered sensitivity of ENaCs to amiloride.--Bai, J., Chow, B. K. C. Secretin is involved in sodium conservation through the renin-angiotensin-aldosterone system. [ABSTRACT FROM AUTHOR]

Secretin, a classical gastrointestinal hormone released from S cells in response to acid and dietary lipid, regulates pleiotropic physiological functions, such as exocrine pancreatic secretion and gastric motility. Subsequent to recently proposed revisit on secretin's metabolic effects, we have confirmed lipolytic actions of secretin during starvation and discovered a hormone-sensitive lipase-mediated mechanistic pathway behind. In this study, a 12 wk high-fat diet (HFD) feeding to secretin receptor-knockout (SCTR-/-) mice and their wild-type (SCTR+/+) litter-mates revealed that, despite similar food intake, SCTRT-/- mice gained significantly less weight (SCTR+/+: 49.6±0.9 g; SCTRT-/-: 44.7±1.4 g; P<0.05) and exhibited lower body fat content. These SCTRT-/- mice have corresponding alleviated HFD-associated hyperleptinemia and improved glucose/insulin tolerance. Further analyses indicate that SCTRT-/- have impaired intestinal fatty acid absorption while having similar energy expenditure and locomotor activity. Reduced fat absorption in the intestine is further supported by lowered postprandial triglyceride concentrations in circulation in SCTR-/- mice. In jejunal cells, transcript and protein levels of a key fat absorption regulator, cluster of differentiation 36 (CD36), was reduced in knockout mice, while transcript of Cd36 and fatty-acid uptake in isolated enterocytes was stimulated by secretin. Based on our findings, a novel positive feedback pathway involving secretin and CD36 to enhance intestinal lipid absorption is being proposed. [ABSTRACT FROM AUTHOR]

Angiotensin (ANGII) and secretin (SCT) share overlapping, interdependent osmoregulatory functions in brain, where SCT peptide/receptor function is required for ANGII action, yet the molecular basis is unknown. Since receptors for these peptides (AT1aR, SCTR) are coexpressed in osmoregulatory centers, a possible mechanism is formation of a cross-class receptor heterocomplex. Here, we demonstrate such a complex and its functional importance to modulate signaling. Association of AT1aR with SCTR reduced ability of SCT to stimulate cyclic adenosine monophosphate (cAMP), with signaling augmented in presence of ANGII or constitutively active AT1aR. Several transmembrane (TM) peptides of these receptors were able to affect their conformation within complexes, reducing receptor BRET signals. AT1aR TM1 affected only formation and activity of the heterocomplex, without effect on homomers of either receptor, and reduced SCT-stimulated cAMP responses in cells expressing both receptors. This peptide was active in vivo by injection into mouse lateral ventricle, thereby suppressing water-drinking behavior after hyperosmotic shock, similar to SCTR knockouts. This supports the interpretation that active conformation of AT1aR is a key modulator of cAMP responses induced by SCT stimulation of SCTR. The SCTR/AT1aR complex is physiologically important, providing differential signaling to SCT in settings of hyperosmolality or food intake, modulated by differences in levels of ANGII. [ABSTRACT FROM AUTHOR]

The functional role of secretin outside the gastrointestinal system has been a mystery to endocrinologists for many years. With the availability of secretin- and secretin receptor-knockout models and the advances of electrophysiological and immunohistochemical techniques, we are now in a good position to explore the functions of secretin outside the gastrointestinal system. There is growing evidence to support that secretin works pleiotropically at multiple levels in our body. In this paper, we review the recent findings regarding the physiological effects of secretin on extragastrointestinal sites including the cerebellum, the hippocampus, and the hypothalamus-pituitary-kidney axis. To understand the mechanisms underlying the site-specific expression of secretin and secretin receptors in the central nervous system, we also discuss the transcriptional regulation of secretin and secretin receptor genes in neuronal cell lines. [ABSTRACT FROM AUTHOR]

Fluid balance is critical to life and hence is tightly controlled in the body. Angiotensin II (ANGII) one of the most important components of this regulatory system, is recognized as a dipsogenic hormone that stimulates vasopressin (VP) expression and release. However, detailed mechanisms regarding how ANGII brings about these changes are not fully understood. In the present study, we show initially that the osmoregulatory functions of secretin (SCT) in the brain are similar to those of ANGII in mice and, more important we discovered the role of SCT-/- as the link between ANGII and its downstream effects. This was substantiated by the use of two knockout mice, SCTR-/- in , SCT-/- in which we show the absence of an intact SCT/secretin receptor (SCTR) axis resulted in and abolishment or much reduced ANGII osmoregulatory functions. By immunohistochemical staining and in situ hybridization, the proteins and transcripts of SCT an its receptor are found in the paraventricular nucleus (PVN) and lamina terminalis. We propose that SCT produced in the circumventricular organs is transported and released in the PVN to stimulate vasopressin expression and release. In summary, our findings identify SCT and SCTR as novel elements of the ANGII osmoregulatory pathway in maintaining fluid balance in the body. [ABSTRACT FROM AUTHOR]

Glucagon and the glucagon-like peptides (GLP-1 and GLP-2) share a common evolutionary origin and are triplication products of an ancestral glucagon exon. In mammals, a standard scenario is found where only a single proglucagon-derived peptide set exists. However, fish and amphibians have either multiple proglucagon genes or exons that are likely resultant of duplication events. Through phylogenetic analysis and examination of their respective functions, the proglucagon ligand-receptor pairs are believed to have evolved independently before acquiring specificity for one another. This review will provide a comprehensive overview of current knowledge of proglucagon-derived peptides and receptors, with particular focus on fish and amphibian species. [ABSTRACT FROM AUTHOR]

As the key regulator of reproduction, gonadotropin-releasing hormone (GnRH) is released by neurons in the hypothalamus, and transported via the hypothalamo-hypophyseal portal circulation to the anterior pituitary to trigger gonadotropin release for gonadal steroidogenesis and gametogenesis. To achieve appropriate reproductive function, mammals have precise regulatory mechanisms; one of these is the control of GnRH synthesis and release. In the past, the scarcity of GnRH neurons and their widespread distribution in the brain hindered the study of GnRH gene expression. Until recently, the development of GnRH-expressing cell lines with properties similar to those of in vivo GnRH neurons and also transgenic mice facilitated GnRH gene regulation research. This minireview provides a summary of the molecular mechanisms for the control of GnRH-I and GnRH-II gene expression. These include basal transcription regulation, which involves essential cis-acting elements in the GnRH-I and GnRH-II promoters and interacting transcription factors, and also feedback control by gonadotropins and gonadal sex steroids. Other physiological stimuli, e.g. insulin and melatonin, will also be discussed. [ABSTRACT FROM AUTHOR]

Gonadotropin-releasing hormone (GnRH) I and II are hypothalamic decapeptides with pivotal roles in the development of reproductive competence and regulation of reproductive events. In this study, transcriptional regulation of the human GnRH II gene was investigated. By scanning mutation analysis coupled with transient promoter assays, the motif at −641/−636 (CATGCC, designated GII-Sil) was identified as a repressor element. Mutation of this motif led to full restoration of promoter activity in TE671 medulloblastoma and JEG-3 placenta choriocarcinoma cells. Supershift and chromatin immunoprecipitation assays showed in vitro and in vivo binding of NF-κB subunit p65 and the retinoic acid receptors, RARα and RXRα, to the promoter sequences. Over-expression of these protein factors indicated that p65 is a potent repressor, and the RARα/RXRα heterodimer is involved in the differential regulation of the GnRH II gene in neuronal and placental cells. This was confirmed by quantitative real-time PCR. Treatment of cells with the RARα/RXRα ligands, all- trans retinoic acid and 9- cis-retinoic acid, reduced and increased GnRH II gene expression in TE671 and JEG-3 cells, respectively. Taken together, these data demonstrate the differential roles of NF-κB p65 and RARα/RXRα, interacting with the same sequence in the promoter of the human GnRH II gene to influence gene expression in a cell-specific manner. [ABSTRACT FROM AUTHOR]

Recent evidence that 5-hydroxytryptamine (5-HT or serotonin) enhances the release and the gene expression of vasopressin and oxytocin in the hypothalamic paraventricular nucleus (PVN) suggests that 5-HT can excite the PVN magnocellular neurons. The objective of this study was to examine the underlying mechanisms for such excitatory action in the electrophysiologically identified hypothalamic PVN magnocellular neurons in rats using whole-cell patch-clamp. We found that 5-HT weakly depolarizes 33.3% of PVN magnocellular neurons in the presence of tetrodotoxin. A minuscule inward current was produced by 5-HT in 48% of the cells, which was attenuated when the 5-HT4 antagonist GR113808 or the 5-HT7 antagonist SB269970 was added. In addition, 5-HT reduced the frequency of miniature inhibitory postsynaptic currents in a dose-dependent manner. This inhibition was mimicked by the 5-HT1B agonist CP93129, and reversed in the presence of 5-HT1B antagonists cyanopindolol and SB224289. Besides, 5-HT induced a biphasic effect on the frequency of miniature excitatory postsynaptic currents, comprising a transient inhibition and a delayed concentration-dependent excitation (onset latency ∼ 5 min). The facilitation was mimicked by the 5-HT2A/2C agonist DOI and abolished in the presence of the 5-HT2C antagonist RS102221. Our findings reveal that 5-HT directly increases the excitability of the PVN magnocellular neurons via multiple receptor subtypes and mechanisms. This may help understanding the regulation of 5-HT-induced hormone release and feeding behavior in the PVN. [ABSTRACT FROM AUTHOR]

Chronic spontaneous urticaria (CSU), atopic dermatitis (AD), psoriasis and rosacea are highly prevalent inflammatory skin conditions which impose a significant burden on patients' quality of life. Their pathophysiology is likely multifactorial, involving genetic, immune and environmental factors. Recent advancements in the field have demonstrated the key role of mast cells (MC) in the pathophysiology of these conditions. The Mas‐related G protein‐coupled receptor X2 (MRGPRX2) has emerged as a promising non‐IgE‐mediated MC activation receptor. MRGPRX2 is predominately expressed on MC and activated by endogenous and exogenous ligands, leading to MC degranulation and release of various pro‐inflammatory mediators. Mounting evidence on the presence of endogenous MRGPRX2 agonists (substance P, cortistatin‐14, LL37, PAMP‐12 and VIP) and its high expression among patients with CSU, AD, rosacea, psoriasis and chronic pruritus emphasizes the pathogenic role of MRGPRX2 in these conditions. Despite the currently available treatments, there remains a pressing need for novel drug targets and treatment options for these chronic inflammatory skin conditions. Here, we reviewed the pathogenic role of MRGPRX2 and its potential as a novel therapeutic target and provided an update on future research directions. [ABSTRACT FROM AUTHOR]

This research letter discusses the potential use of MRGPRX2 and CCL-2 as biomarkers for chronic spontaneous urticaria (CSU) in Chinese patients. The study found that serum MRGPRX2 levels were higher in patients with severe disease compared to nonsevere disease, and that MRGPRX2 was more useful in treatment-naïve patients. Additionally, CCL-2 levels were found to be elevated in patients with severe disease. The study suggests that both MRGPRX2 and CCL-2 may be potential biomarkers for CSU, but further research is needed to validate these findings. [Extracted from the article]

The article reports on the gonadotropin-releasing hormone (GnRH). According to the author, investigations toward the understanding of the role of GnRH in physiological functions, is needed. Furthermore, the author adds that GnRh is also relevan in tumor progresson, as shown by studies on specific cancers. Lastly, the author relates the connection between ovarian cancer and GnRH receptor.