Inhibition of corticotropin-releasing hormone receptor 1 and activation of receptor 2 protect against colonic injury and promote epithelium repair.
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ABSTRACT:
SUBMITTER: Li B
PROVIDER: S-EPMC5425914 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Heart failure occurs when the heart is unable to effectively pump blood and maintain tissue perfusion. Despite numerous therapeutic advancements over previous decades, the prognosis of patients with chronic heart failure remains poor, emphasizing the need to identify additional pathophysiological factors. Here, we show that corticotropin releasing hormone receptor 2 (Crhr2) is a G protein-coupled receptor highly expressed in cardiomyocytes and continuous infusion of the Crhr2 agonist, urocortin 2 (Ucn2), reduced left ventricular ejection fraction in mice. Moreover, plasma Ucn2 levels were 7.5-fold higher in patients with heart failure compared to those in healthy controls. Additionally, cardiomyocyte-specific deletion of Crhr2 protected mice from pressure overload-induced cardiac dysfunction. Mice treated with a Crhr2 antagonist lost maladaptive 3'-5'-cyclic adenosine monophosphate (cAMP)-dependent signaling and did not develop heart failure in response to overload. Collectively, our results indicate that constitutive Crhr2 activation causes cardiac dysfunction and suggests that Crhr2 blockade is a promising therapeutic strategy for patients with chronic heart failure.
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Project description:Cotricotropin-releasing hormone (CRH) and related peptides are produced in skin that is dependent on species and anatomical location. Local peptide production is regulated by ultraviolet radiation (UVR), glucocorticoids and phase of the hair cycle. The skin also expresses the corresponding receptors (CRH-R1 and CRH-R2), with CRH-R1 being the major receptor in humans. CRH-R1 is expressed in epidermal and dermal compartments, and CRH-R2 predominantly in dermal structures. The gene coding for CRH-R1 generates multiple isoforms through a process modulated by UVR, cyclic adenosine monophosphate (cAMP) and phorbol 12-myristate 13-acetate. The phenotypic effects of CRH in human skin cells are largely mediated by CRH-R1alpha through increases in concentrations of cAMP, inositol triphosphate (IP3), or Ca2+ with subsequent activation of protein kinases A (PKA) and C (PKC) dependent pathways. CRH also modulates the activity of nuclear factor of kappa light polypeptide gene enhancer in B-cells (NF-kappaB), activator protein 1 (AP-1) and cAMP responsive element binding protein (CREB). The cellular functions affected by CRH depend on cell type and nutritional status and include modulation of differentiation program(s), proliferation, viability and immune activity. The accumulated evidence indicates that cutaneous CRH is also a component of a local structure organized similarly to the hypothalamo-pituitary-adrenal axis.
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Project description:BACKGROUND: Corticotropin-releasing hormone (CRH) acts mainly via the CRH receptor 1 (CRH-R1) and plays a crucial role in the stress-induced pathophysiology of irritable bowel syndrome (IBS). Several studies have demonstrated that variants of the CRH-R1 gene carry a potential risk for depression, but evidence for an association between CRH-R1 genotypes and IBS is lacking. We tested the hypothesis that genetic polymorphisms and haplotypes of CRH-R1 moderate the IBS phenotype and negative emotion in IBS patients. METHODS: A total of 103 patients with IBS and 142 healthy controls participated in the study. Three single-nucleotide polymorphisms of the CRH-R1 gene (rs7209436, rs242924, and rs110402) were genotyped. Subjects' emotional states were evaluated using the Perceived-Stress Scale, the State-Trait Anxiety Inventory, and the Self-rating Depression Scale. RESULTS: The TT genotype of rs7209436 (P = 0.01) and rs242924 (P = 0.02) was significantly more common in patients with IBS than in controls. Total sample analysis showed significant association between bowel pattern (normal, diarrhea, constipation, or mixed symptoms) and the T allele of rs7209436 (P = 0.008), T allele of rs242924 (P = 0.019), A allele of rs110402 (P = 0.047), and TAT haplocopies (P = 0.048). Negative emotion was not associated with the examined CRH-R1 SNPs. CONCLUSION: These findings suggest that genetic polymorphisms and the CRH-R1 haplotypes moderate IBS and related bowel patterns. There was no clear association between CRH-R1 genotypes and negative emotion accompanying IBS. Further studies on the CRH system are therefore warranted.
| S-EPMC3434156 | biostudies-literature
Project description:Corticotropin-releasing hormone (CRH) plays an important role in the pathophysiology of irritable bowel syndrome (IBS) and regulates the stress response through two CRH receptors (R1 and R2). Previously, we reported that a CRHR1 gene polymorphism (rs110402, rs242924, and rs7209436) and haplotypes were associated with IBS. However, the association between the CRHR2 gene and IBS was not investigated. We tested the hypothesis that genetic polymorphisms and haplotypes of CRHR2 are associated with IBS pathophysiology and negative emotion in IBS patients.A total of 142 IBS patients and 142 healthy controls participated in this study. Seven single nucleotide polymorphisms (SNPs) of the CRHR2 gene (rs4722999, rs3779250, rs2240403, rs2267710, rs2190242, rs2284217, and rs2284220) were genotyped. Subjects' psychological states were evaluated using the Perceived-Stress Scale, the State-Trait Anxiety Inventory, and the Self-Rating Depression Scale.We found that rs4722999 and rs3779250, located in intronic region, were associated with IBS in terms of genotype frequency (rs4722999: P = 0.037; rs3779250: P = 0.017) and that the distribution of the major allele was significantly different between patients and controls. There was a significant group effect (controls vs. IBS), and a CRHR2 genotype effect was observed for three psychological scores, but the interaction was not significant. We found a haplotype of four SNPs (rs4722999, rs3779250, rs2240403, and rs2267710) and two SNPs (rs2284217 and rs2284220) in strong linkage disequilibrium (D' > 0.90). We also found that haplotypes of the CRHR2 gene were significantly different between IBS patients and controls and that they were associated with negative emotion.Our findings support the hypothesis that genetic polymorphisms and haplotypes of CRHR2 are related to IBS. In addition, we found associations between CRHR2 genotypes and haplotypes and negative emotion in IBS patients and controls. Further studies on IBS and the CRH system are warranted.
| S-EPMC4726564 | biostudies-literature
Project description:Urocortin 3 (UCN3) is strongly expressed in specific nuclei of the rodent brain, at sites distinct from those expressing urocortin 1 and urocortin 2, the other endogenous ligands of corticotropin-releasing hormone receptor type 2 (CRH-R2). To determine the physiological role of UCN3, we generated UCN3-deficient mice, in which the UCN3 open reading frame was replaced by a tau-lacZ reporter gene. By means of this reporter gene, the nucleus parabrachialis and the premammillary nucleus were identified as previously unknown sites of UCN3 expression. Additionally, the introduced reporter gene enabled the visualization of axonal projections of UCN3-expressing neurons from the superior paraolivary nucleus to the inferior colliculus and from the posterodorsal part of the medial amygdala to the principal nucleus of the bed nucleus of the stria terminalis, respectively. The examination of tau-lacZ reporter gene activity throughout the brain underscored a predominant expression of UCN3 in nuclei functionally connected to the accessory olfactory system. Male and female mice were comprehensively phenotyped but none of the applied tests provided indications for a role of UCN3 in the context of hypothalamic-pituitary-adrenocortical axis regulation, anxiety- or depression-related behavior. However, inspired by the prevalent expression throughout the accessory olfactory system, we identified alterations in social discrimination abilities of male and female UCN3 knock-out mice that were also present in male CRH-R2 knock-out mice. In conclusion, our results suggest a novel role for UCN3 and CRH-R2 related to the processing of social cues and to the establishment of social memories.
| S-EPMC6632482 | biostudies-literature
Project description:Corticotropin-releasing hormone (CRH) is a key regulator of the mammalian stress response, mediating a wide variety of stress-associated behaviors including stress-induced inhibition of reproductive function. To investigate the potential direct action of CRH on pituitary gonadotrope function, we examined CRH receptor expression and second messenger signaling in alpha T3-1 cells, a murine gonadotrope-like cell line. Reverse transcriptase PCR (RT-PCR) studies demonstrated that alpha T3-1 cells express mRNA for the two CRH receptor subtypes, CRHR1 and CRHR2, with CRHR2alpha as the predominant CRHR2 isoform. Stimulation of the cells with CRH or urocortin (UCN) resulted in rapid, transient increases in the intracellular levels of cAMP that were completely blocked by the addition of alpha-helical CRH 9-41 or astressin, non-selective CRH receptor antagonists. Stimulation of the cells with CRHR2-specific ligands, urocortin 2 (UCN2) or urocortin 3 (UCN3), resulted in rapid increases in intracellular cAMP levels to 50-60% of the levels observed with UCN. Treatment with a selective CRHR2 antagonist, antisauvagine, completely blocked UCN3-mediated increases in cAMP and significantly reduced, but did not completely block UCN-mediated increases in cAMP, demonstrating that both CRHR1 and CRHR2 are functionally active in these gonadotrope-like cells. Finally, UCN treatment significantly increased the transcriptional activity of the glycoprotein hormone alpha-subunit promoter as assessed by alpha-luciferase transfection assays. Together, these results demonstrate the functional signaling of CRH receptors in alpha T3-1 cells, suggesting that CRH may also modulate pituitary gonadotrope function in vivo.
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Project description:Our aim was to investigate whether a genetic variation in the corticotropin-releasing hormone receptor 2 gene might be associated with preterm birth. In this case-control study we evaluated the G/A polymorphism (rs2267717) in intron 2 of the corticotropin-releasing hormone receptor 2 gene in one hundred women with preterm birth and one hundred healthy women with at least one uncomplicated full term pregnancy and no history of preterm birth. No significant correlation was found between the presence of the investigated polymorphism and preterm birth (p=0.9, odds ratio 0.9 [Confidence interval 0.5-1.7]). A dose dependent association of the investigated polymorphism, in women with preterm birth, with gestational age at delivery (p=0.003) and birth weight was observed (p=0.0001). However, no association between IUGR (n=10) with either one of the investigated genotypes (p=0.3) was found. Stratified analysis within case group (i.e. PPROM vs. non-PPROM) revealed no significant difference in genotype distribution (p=0.6). In conclusion, the investigated polymorphism does not increase the risk for preterm birth overall but might modulate the length of pregnancy in a dose dependent fashion in a series of Caucasian women.
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Project description:Endometriosis is a disorder in which endometrial tissue is found outside the uterus causing pain, infertility and stress. Finding effective, non-hormonal and long-term treatments for endometriosis still remains one of the most significant challenges in the field. Corticotropin releasing hormone (CRH) is one of the main signaling peptides within the hypothalamic pituitary adrenal (HPA) axis released in response to stress. CRH can affect nervous and visceral tissues such as the uterus and gut via activation of two types of CRH receptors: CRHR1 and CRHR2. Our aim was to determine if blocking CRHR1 with antalarmin will reduce endometriosis progression. In experiment 1 we induced endometriosis in female rats by suturing uterine horn tissue next to the intestinal mesentery and allowed to progress for 7 days. We determined that after 7 days, there was a significant increase in CRHR1 within endometriotic vesicles as compared to normal uterus. In Experiment 2, we induced endometriosis and administered either antalarmin (20 mg/kg, i.p.) or vehicle during the first 7 days after surgery. A separate group of sham surgery rats served as non-endometriosis controls. Endometriosis was allowed to progress until 60 days after surgery, at which time rats were tested for anxiety behaviors. At the time of sacrifice, endometriotic vesicles, uterus and blood were collected. Treatment with antalarmin significantly reduced the size (67% decrease) and number (30% decrease) of endometriotic vesicles. Antalarmin also prevented the increase in CRH and CRHR1 mRNA within endometriotic vesicles but not of glucocorticoid receptor. Endometriosis did not change anxiety behaviors in the open field and zero-maze tests and prior antalarmin administration did not modify this. Our data provides the first in-vivo demonstration for use of CRHR1 antagonist for the treatment of endometriosis opening the possibility for further exploring CRH signaling as a treatment target for this debilitating disease.
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Project description:Because an acidic cellular microenvironment is engendered by inflammation and may determine cell differentiation, we elucidated the impact of acidic conditions on induction of proopiomelanocortin (POMC) expression. Here, we demonstrate mechanisms for proton sensitivity of CRH receptor 1 (CRHR1) signaling to POMC and ACTH production. Low pH (6.8) resulted in doubling of POMC expression and ACTH production in pituitary cell line AtT-20 and in primary mouse pituitary cells. Using CRISPR knockout, we show that CRHR1 is necessary for acid-induced POMC expression, and this induction is mediated by CRHR1 histidine residues and calmodulin-dependent protein kinase II in both pituitary corticotroph cells and in nonpituitary cell lines expressing ectopic ACTH. In contrast, CRH ligand binding affinity to CRHR1 was decreased with acidic pH, implying that proton-induced POMC expression prevails in acidic conditions independently of CRH ligand binding. The results indicate that proton-induced CRHR1 signaling regulates ACTH production in response to an acidic microenvironment.
| S-EPMC6324021 | biostudies-literature
Project description:We completed the mapping of a cutaneous CRH signaling system in two species with widely different determinants of skin functions, humans and mice. In human skin, the CRH receptor (CRH-R) 1 was expressed in all major cellular populations of epidermis, dermis, and subcutis with CRH-R1alpha being the most prevalent isoform. The CRH-R2 gene was expressed solely in hair follicle keratinocytes and papilla fibroblasts, whereas CRH-R2 antigen was localized predominantly in hair follicles, sebaceous and eccrine glands, muscle and blood vessels. In mouse skin, the CRH-R2 gene and protein were widely expressed in all cutaneous compartments and in cultured normal and malignant melanocytes. CRH-binding protein mRNA was present in dermal fibroblasts, melanoma cells, and sc fat of human skin and undetectable in mouse skin. The urocortin II gene was expressed equally in mouse and human skin. Taken together with our previous investigations, the present studies document the preferential expression of CRH-R1 in human skin, which mirrors CRH-R2 expression patterns in human and mouse skin. They are likely reflecting different functional activities of human and mouse skin. The adnexal location of CRH-R2 suggests a role for the receptor in hair growth. The differential interspecies CRH signaling expression pattern probably reflects adaptation to species-specific skin function determinants.
| S-EPMC1201495 | biostudies-literature