Corticotropin-releasing Hormone Receptor Subtypes Research Articles

Targeted overexpression of CRH receptor subtype 1 in central amygdala neurons: effect on alcohol-seeking behavior.

The corticotropin-releasing hormone (CRH) system is a key mediator of stress-induced responses in alcohol-seeking behavior. Recent research has identified the central nucleus of the amygdala (CeA), a brain region involved in the regulation of fear and stress-induced responses that is especially rich in CRH-positive neurons, as a key player in mediating excessive alcohol seeking. However, detailed characterization of the specific influences that local neuronal populations exert in mediating alcohol responses is hampered by current limitations in pharmacological and immunohistochemical tools for targeting CRH receptor subtype 1 (CRHR1). In this study, we investigated the effect of cell- and region-specific overexpression of CRHR1 in the CeA using a novel transgenic tool. Co-expression of CRHR1 in calcium-calmodulin-dependent kinase II (αCaMKII) neurons of the amygdala was demonstrated by double immunohistochemistry using a Crhr1-GFP reporter mouse line. A Cre-inducible Crhr1-expressing adeno-associated virus (AAV) was site-specifically injected into the CeA of αCaMKII-CreERT2 transgenic rats to analyze the role of CRHR1 in αCaMKII neurons on alcohol self-administration and reinstatement behavior. Forty-eight percent of CRHR1-containing cells showed co-expression of αCaMKII in the CeA. AAV-mediated gene transfer in αCaMKII neurons induced a 24-fold increase of Crhr1 mRNA in the CeA which had no effect on locomotor activity, alcohol self-administration, or cue-induced reinstatement. However, rats overexpressing Crhr1 in the CeA increased responding in the stress-induced reinstatement task with yohimbine serving as a pharmacological stressor. We demonstrate that CRHR1 overexpression in CeA-αCaMKII neurons is sufficient to mediate increased vulnerability to stress-triggered relapse into alcohol seeking.

Dissociable Role of Corticotropin Releasing Hormone Receptor Subtype 1 on Dopaminergic and D1 Dopaminoceptive Neurons in Cocaine Seeking Behavior.

The ability of many drugs of abuse, including cocaine, to mediate reinforcement and drug-seeking behaviors is in part mediated by the corticotropin-releasing hormone (CRH) system, in which CRH exerts its effects partly via the CRH receptor subtype 1 (CRHR1) in extra-hypothalamic areas. In fact, CRHR1 expressed in regions of the mesolimbic dopamine (DA) system have been demonstrated to modify cocaine-induced DA release and alter cocaine-mediated behaviors. Here we examined the role of neuronal selectivity of CRHR1 within the mesolimbic system on cocaine-induced behaviors. First we used a transgenic mouse line expressing GFP under the control of the Crhr1 promoter for double fluorescence immunohistochemistry to demonstrate the cellular location of CRHR1 in both dopaminergic and D1 dopaminoceptive neurons. We then studied cocaine sensitization, self-administration, and reinstatement in inducible CRHR1 knockouts using the CreERT2/loxP in either dopamine transporter (DAT)-containing neurons (DAT-Crhr1) or dopamine receptor 1 (D1)-containing neurons (D1-Crhr1). For sensitization testing, mice received five daily injections of cocaine (15 mg/kg IP). For self-administration, mice received eight daily 2 h cocaine (0.5 mg/kg per infusion) self-administration sessions followed by extinction and reinstatement testing. There were no differences in the acute or sensitized locomotor response to cocaine in DAT-Crhr1 or D1-Crhr1 mice and their respective controls. Furthermore, both DAT-Crhr1 and D1-Crhr1 mice reliably self-administered cocaine at the level of controls. However, DAT-Crhr1 mice demonstrated a significant increase in cue-induced reinstatement relative to controls, whereas D1-Crhr1 mice demonstrated a significant decrease in cue-induced reinstatement relative to controls. These data demonstrate the involvement of CRHR1 in cue-induced reinstatement following cocaine self-administration, and implicate a bi-directional role of CRHR1 for cocaine craving.

Cross-talk of corticotropin-releasing hormone receptor subtype 1 with dopamine D1 receptor: functional relevance in alcohol dependence

Cross-talk of corticotropin-releasing hormone receptor subtype 1 with dopamine D1 receptor: functional relevance in alcohol dependence

Corticotropin-Releasing Hormone Receptor 1 Antagonist With or Without Corticotropin-Releasing Hormone Receptor 2 Remain Promising in Relieving Human Acute Psychological Stress and Related Intestinal Hyperpermeability

Corticotropin-releasing hormone (CRH) has clinical relevant to stress, feeding behavior, gut motility and immunity. Emerging evidence indicates that two CRH receptor subtypes, receptor 1 (CRH1-R) and 2 (CRH2-R), play pivotal roles in the regulation of these biological functions induced by CRH, depending on which receptor subtypes to be activated. Manipulating and balancing at CRH1-R and CRH2-R has become a novel concept to treat stress-related disorders and gut dysfunction, such as psychological stress and related intestinal hyperpermeability.

Differential expression of CRH, UCN, CRHR1 and CRHR2 in eutopic and ectopic endometrium of women with endometriosis.

Endometriosis is considered as a benign aseptic inflammatory disease, characterised by the presence of ectopic endometrium-like tissue. Its symptoms (mostly pain and infertility) are reported as constant stressors. Corticotropin releasing hormone (CRH) and urocortin (UCN) are neuropeptides, strongly related to stress and inflammation. The effects of CRH and UCN are mediated through CRHR1 and CRHR2 receptors which are implicated in several reproductive functions acting as inflammatory components. However, the involvement of these molecules to endometriosis remains unknown. The aim of this study was to examine the expression of CRHR1 and CRHR2 in endometriotic sites and to compare the expression of CRHR1 and CRHR2 in eutopic endometrium of endometriotic women to that of healthy women. We further compared the expression of CRH, UCN, CRHR1 and CRHR2 in ectopic endometrium to that in eutopic endometrium of women with endometriosis. Endometrial biopsy specimens were taken from healthy women (10 patients) and endometrial and endometriotic biopsy specimens were taken from women with endometriosis (16 patients). Τhe expression of CRH, UCN, CRHR1, and CRHR2 was tested via RT-PCR, immunohistochemistry and Western blotting. This study shows for the first time that CRH and UCN receptor subtypes CRHR1β and CRHR2α are expressed in endometriotic sites and that they are more strongly expressed (p<0.01) in eutopic endometrium of women with endometriosis compared to healthy women endometrium at the mRNA and protein level. CRH, UCN, CRHR1 and CRHR2 mRNA were also more highly expressed in ectopic rather than eutopic endometrium (CRH, UCN, CRHR2α: p<0.01, CRHR1β: p<0.05) and protein (CRH and UCN: p<0.05, CRHR1 and CRHR2: p<0.01) in women with endometriosis. These data indicate that CRH and UCN might play an immunoregulatory role in endometriotic sites by affecting reproductive functions such as decidualization and implantation of women with endometriosis.

Mapping Structural Determinants within Third Intracellular Loop That Direct Signaling Specificity of Type 1 Corticotropin-releasing Hormone Receptor

The type 1 corticotropin-releasing hormone receptor (CRH-R1) influences biological responses important for adaptation to stressful stimuli, through activation of multiple downstream effectors. The structural motifs within CRH-R1 that mediate G protein activation and signaling selectivity are unknown. The aim of this study was to gain insights about important structural determinants within the third intracellular loop (IC3) of the human CRH-R1α important for cAMP and ERK1/2 pathways activation and selectivity. We investigated the role of the juxtamembrane regions of IC3 by mutating amino acid cassettes or specific residues to alanine. Although simultaneous tandem alanine mutations of both juxtamembrane regions Arg(292)-Met(295) and Lys(311)-Lys(314) reduced ligand binding and impaired signaling, all other mutant receptors retained high affinity binding, indistinguishable from wild-type receptor. Agonist-activated receptors with tandem mutations at the proximal or distal terminal segments enhanced activation of adenylyl cyclase by 50-75% and diminished activation of inositol trisphosphate and ERK1/2 by 60-80%. Single Ala mutations identified Arg(292), Lys(297), Arg(310), Lys(311), and Lys(314) as important residues for the enhanced activation of adenylyl cyclase, partly due to reduced inhibition of adenylyl cyclase activity by pertussis toxin-sensitive G proteins. In contrast, mutation of Arg(299) reduced receptor signaling activity and cAMP response. Basic as well as aliphatic amino acids within both juxtamembrane regions were identified as important for ERK1/2 phosphorylation through activation of pertussis toxin-sensitive G proteins as well as G(q) proteins. These data uncovered unexpected roles for key amino acids within the highly conserved hydrophobic N- and C-terminal microdomains of IC3 in the coordination of CRH-R1 signaling activity.

CRH-R1 and CRH-R2 differentially modulate dendritic outgrowth of hippocampal neurons

Corticotropin-releasing hormone (CRH) has been implicated to be involved in the development of dendrites in brain. In the present study, we examined the effect of CRH on dendrite outgrowth in primary cultured hippocampal neurons and defined the specific CRH receptor subtype involved. Treatment of neurons with increasing concentration of CRH resulted in an increase in the total dendritic branch length (TDBL) of neurons compared with untreated neurons over 2-4days period of treatment. These effects can be reversed by the specific CRH-R1 antagonist antalarmin but not by the CRH-R2 antagonist astressin 2B. Treatment of neurons with urocortin II, the exclusive CRH-R2 agonist, significantly decreased TDBL of the cultured neurons. These effects can be reversed by the CRH-R2 antagonist astressin 2B. Our results suggest that CRH-R1 and CRH-R2 differentially modulate the dendritic growth of hippocampal neurons in culture.

The CRH-R1 receptor mediates luteinizing hormone, prolactin, corticosterone and progesterone secretion induced by restraint stress in estrogen-primed rats

Acute stress has been shown to modify hypothalamus–pituitary–gonadal (HPG) axis activity. Corticotropin-releasing hormone (CRH), the principal regulator of the hypothalamus–pituitary–adrenal (HPA) axis, has been implicated as a mediator of stress-induced effects on the reproductive axis. The role of the specific CRH receptor subtypes in this response is not completely understood. In the current study, we investigated the role of the CRH-R1 receptor on luteinizing hormone (LH), follicle-stimulating hormone (FSH), prolactin (PRL), progesterone (P) and corticosterone (CT) secretion in stress-induced responses under the influence of estrogen (E2). Estrogen-primed ovariectomized rats (estradiol cypionate, 10μg sc) received an i.v. administration of antalarmin (0.1 or 1mg/kg), a selective CRH-R1 antagonist, or vehicle before restraint stress for 40min. Seven blood samples were collected from two experimental groups (one from 10:00h to 14:00h and the other from 10:00h to 18:00h). An increase of plasma LH induced by restraint acute-stress was followed by alteration of the secretion pattern in the estrogen-induced afternoon surge. In a similar manner, we observed a suppression of the afternoon surge in plasma FSH, a delay of E2-induced PRL secretion, and an increase in plasma P and CT. Antalarmin attenuated stress-induce LH increase, decreased CT and P secretion and blocked the stress effects on PRL secretion. These findings suggest that CRH-R1 mediates, at least in part, the restraint stress effects on the HPA, PRL, and reproductive axes.

Corticotropin‐Releasing Hormone and Mast Cells in the Regulation of Mucosal Barrier Function in the Human Colon

Corticotropin-releasing hormone (CRH) is an important neuro-endocrine mediator of the stress response. Local effects of CRH in the intestinal mucosa have become evident in recent years. We showed that CRH activates CRH receptor subtypes R1 and R2 on subepithelial mast cells, thereby inducing increased transcellular uptake of protein antigens in human colonic biopsies in Ussing chambers. Ongoing studies also implicate local cholinergic signaling in regulation of macromolecular permeability in the human colon. Since increased uptake of antigenic molecules is associated with mucosal inflammation, our findings may have implications for understanding stress-related intestinal disorders.

Corticotropin-releasing hormone receptor expression and functional signaling in murine gonadotrope-like cells

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.

Corticotropin-releasing hormone (CRH) regulates macromolecular permeability via mast cells in normal human colonic biopsies in vitro

Objective:Persistent stress and life events affect the course of ulcerative colitis and irritable bowel syndrome by largely unknown mechanisms. Corticotropin-releasing hormone (CRH) has been implicated as an important mediator of...

A Role for Type 1α Corticotropin-Releasing Hormone Receptors in Mediating Local Changes in Chronically Inflamed Tissue

Peripheral corticotropin-releasing hormone (CRH) is an important regulator of localized inflammatory responses. The aim of this study is to define the pathological signaling pathways in which peripheral CRH receptor-mediated responses reside. We report that PECAM-1-expressing synovial membrane endothelial cells are the principal source of CRH receptor subtype 1alpha in chronically inflamed synovial tissue (ST). Analysis of ST from an early arthritis patient cohort (n = 9) established that expression of CRH-R1alpha significantly (P < 0.03) colocalized with PECAM-1 and E-selectin expression in vivo. Freshly excised ST explants released a mediator(s) that acts to promote CRH-R1alpha mRNA to levels present in inflamed human synovium (n = 8). We tested the ability of conditioned medium and individual inflammatory mediators to modulate CRH-R1alpha expression. Histamine selectively induced the expression of CRH-R1alpha, and these effects were mediated through the histamine receptor type 1. Ectopic expression of CRH-R1alpha in normal human endothelial and synoviocyte cells resulted in the induction of the orphan receptor NR4A2 through the reconstitution of cAMP/protein kinase A/cAMP response element-binding protein signaling and identified a role for CRH in modulating nuclear factor kappaB transcriptional activity. CRH enhanced the expression of nitric-oxide synthase (NOS III) to promote NO production from CRH-R1alpha-expressing cells. These data establish a role for CRH receptor-mediated responses in regulating vascular changes associated with chronic synovitis.

Effects of corticotropin-releasing hormone (CRH) on endothelin-1 and NO release, mediated by CRH receptor subtype R2: A potential link between stress and endothelial dysfunction?

Objective Psychosocial factors, associated with elevated corticotropin releasing hormone (CRH) concentrations, have been reported to be independently associated with coronary heart disease. Methods Endothelin-1 and NO release of human endothelial cells were quantified via ELISA or fluorometrically after treatment with CRH. CRH-receptor subtype 2 (CRH-R2) was visualized on endothelial cells by immunohistochemistry and confirmed by polymerase chain reaction using CRH-R2 primers. Results CRH induced a significant increase of ET-1 release, and the effect was abolished by the CRH-receptor antagonist astressin. The effect was mediated by CRH-R2. In contrast, NO release was not affected. Conclusion CRH-R2 is expressed on human endothelial cells, mediating the CRH-induced stimulation of ET-1 release, whereas NO release is not affected. Thus, peripherally circulating CRH may offset the balance between endothelial vasoconstrictor and vasodilator release with unopposed vasoconstriction. Our data may provide a new concept on how CRH-receptor antagonists may prevent CRH-induced disorders of vascular biology.

The CRH1 antagonist CP154,526 failed to alter ischemia-induced neurodegeneration and spatial memory deficits in rats but inhibited behavioral activity in the novel open field

Corticotropin-releasing hormone (CRH) has been implicated in ischemia-induced neurotoxicity, due in part to excitatory effects at the hippocampus, and the demonstrated neuroprotective effects of centrally administered, non-specific CRH antagonists. However, a number of issues remain to be clarified from these studies, including the relative contribution of CRH receptor subtypes, and the efficacy of these compounds to alter ischemia-induced behavioral impairments. In the current study, a highly selective, systemically administered CRH1 antagonist (CP154,526) failed to reverse global ischemia-induced cell death in hippocampal CA1 neurons or spatial memory impairments as assessed in the radial arm maze. Similarly, central administration of α-helical CRH failed to confer protection against ischemic damage. Interestingly, CRH1 antagonism reversed ischemia-induced hyperactivity in a novel open field, suggesting that modulation of this behavior is independent of effects on hippocampal CA1 cell loss. Failure of the current study to demonstrate neuroprotective effects of either the selective or non-selective CRH antagonists tested challenges the proposed neurotoxic role of CRH in global ischemia. These findings are discussed in relationship to recent findings reconsidering the participation of CRH in excitotoxic-mediated cellular damage.

Corticotropin-Releasing Hormone (CRH) and Urocortin Act through Type 1 CRH Receptors to Stimulate Dehydroepiandrosterone Sulfate Production in Human Fetal Adrenal Cells

Near term, the human fetal adrenal increases the production of cortisol and dehydroepiandrosterone sulfate (DHEAS). DHEAS, which acts as substrate for placental estrogen production, induces key changes involved in parturition. The objective of this study was to determine quantitatively the effect of CRH on mRNA levels of enzymes needed for DHEAS production (steroidogenic acute regulatory protein, CYP11A, CYP17, and SULT2A1), to determine the CRH receptor (CRH-R) subtype(s) responsible for CRH action, and to determine the effect of CRH on CRH-R mRNA expression in human adrenal fetal zone (FZ) cells. Human adrenal FZ cells were treated with CRH, ACTH, urocortin (Unc), and CRH antagonists, and RNA was analyzed by microarray and real-time RT-PCR. This study was performed at an academic research laboratory. The main outcome measure was the expression of steroidogenic enzymes and CRH-R. Microarray analysis of human FZ cells treated for 24 h with CRH or ACTH showed increased mRNA expression levels of the genes needed for DHEAS production. Real-time RT-PCR analysis confirmed these data. Induction was lost in the presence of CRH-R1 antagonists, but not CRH-R2 antagonists. Stimulation was reproduced by Unc. The CRH-R1alpha mRNA splice variant was the only type 1 receptor isoform expressed in the fetal adrenal, and treatment with CRH up-regulates its mRNA levels. CRH, Unc, and ACTH stimulate all elements of the DHEAS synthetic pathway and activate CRH-R1 as well. The resulting increased DHEAS levels can be used for placental estrogen synthesis and contribute to the process leading to parturition in humans.

CRH-Stimulation of Cyclic Adenosine 5'-Monophosphate Pathway Is Partially Inhibited by the Coexpression of CRH-R1 and CRH-R2α

Corticotropin-releasing hormone (CRH) is one of the major proteins responsible for brain stress regulation. Two well-known receptors have been described: type 1 and type 2alpha, both members of the receptor superfamily of G protein-coupled receptors (GPCR). We investigated receptor regulation when both CRH receptor subtypes are coexpressed in the same mammalian cell line. When both types of receptors are coexpressed, cAMP second messenger production is partially inhibited compared to when receptors are expressed separately. However, neither binding kinetics nor internalization rates are modified by coexpression of these receptors. To our knowledge this is the first demonstration of receptor interaction that results in the modification of CRH-mediated signal transduction pathway. Because CRH-R1 and CRH-R2alpha have overlapping mRNA expression patterns in the brain, these receptors may be coexpressed in neurons, suggesting that receptor interaction may play an important role in the effect evoked by CRH, contributing to the complexity of differential coupling of the CRH receptors in different endocrine and stress behavior responses.

Involvement of corticotropin-releasing hormone receptor subtypes 1 and 2 in peripheral opioid-mediated inhibition of inflammatory pain

In painful inflammation, exogenous as well as endogenous corticotropin-releasing hormone (CRH) can release opioid peptides (mainly β-endorphin) from various types of immune cells and produce antinociception by activating opioid receptors on peripheral sensory nerve endings. CRH mediates its central effects through two high-affinity membrane receptors, the CRH receptor subtypes 1 and 2. It is unclear at present whether the peripheral antinociceptive effects of CRH are mediated through CRH receptor 1 (CRH R1) or CRH receptor 2 (CRH R2). Employing a double-immunocytochemical technique, this study investigated in Wistar rats with Freund's complete adjuvant-induced hind paw inflammation whether immune cells within blood and inflamed subcutaneous tissue express CRH R1 and/or CRH R2 together with the opioid peptide β-endorphin (END). Additionally, we examined using selective CRH R1 and CRH R2 antagonists whether peripheral CRH-induced antinociception is mediated by the respective CRH receptor subtypes. We found a high degree of co-expression of END together with both CRH R1 and CRH R2 in macrophage/monocytes, granulocytes and lymphocytes within blood and inflamed subcutaneous tissue. Also we observed a high degree of co-localization of CRH R1 and CRH R2 receptors on circulating and resident immune cells. Both the selective CRH R1 antagonist CP-154,526 and the selective CRH R2 antagonist astressin 2B significantly attenuated peripheral antinociceptive effects of CRH indicating the involvement of both CRH receptor subtypes. Taken together, these findings suggest that in inflammatory pain CRH-induced peripheral antinociception is mediated via both CRH R1 and CRH R2 located on END containing immune cells within inflamed sites.

Corticotropin Releasing Hormone Type 2 Receptors in the Dorsal Raphe Nucleus Mediate the Behavioral Consequences of Uncontrollable Stress

Uncontrollable shock produces a constellation of behavioral changes that are not observed after equivalent escapable shock. These include interference with escape and potentiation of fear conditioning. The activation of corticotropin-releasing hormone (CRH) receptors within the caudal dorsal raphe nucleus (DRN) during inescapable tailshock (IS) has been shown to be critical for the development of these behavioral changes. CRH binds to two receptor subtypes, both of which are found in the DRN. The present set of studies examined which CRH receptor subtype mediates the effects of IS. Intra-DRN administration of the CRH(2) receptor antagonist anti-sauvagine-30 before IS dose-dependently blocked IS-induced behavioral changes; the CRH(1) receptor antagonist 2-methyl-4-(N-propyl-N-cycloproanemethylamino)-5-chloro-6-(2,4,6-trichloranilino)pyrimidine (NBI27914), administered in the same manner, did not. Moreover, the highly selective CRH(2) receptor agonist urocortin II (Ucn II) dose-dependently caused behavioral changes associated with IS in the absence of shock. Ucn II was effective at doses 100-fold lower than those previously required for CRH. The relationship between CRH(2) receptors and DRN 5-HT is discussed.

Corticotropin-releasing hormone antagonists possess anti-inflammatory effects in the mouse ileum

Background & Aims: Corticotropin-releasing hormone (CRH) released at local sites of inflammation promotes inflammation in the periphery. We investigated its effects in the intestinal responses caused by toxin A from Clostridium difficile, the causative agent of antibiotic-associated colitis. Methods: Ileal loops were injected with 10 μg of toxin A, and enterotoxic responses were measured at various time points. Results: Pretreatment of mice with 2.5 μg/kg of the CRH receptor antagonist α-helical CRH(9–41) that blocks both CRH receptor subtypes reduced toxin A–mediated ileal secretion, epithelial cell damage, mucosal edema, neutrophil infiltration, and mucosal content of interleukin 1β and tumor necrosis factor α. Pretreatment with the specific CRH1 receptor antagonist antalarmin (20 mg/kg, IP) also inhibited toxin A–induced fluid secretion and toxin A–associated histologic changes. CRH messenger RNA and protein were increased in mouse ileum 30 minutes after intraluminal toxin A administration. In situ hybridization and immunohistochemistry demonstrated that toxin A at 1 hour caused a substantial increase in the expression of both CRH receptor subtypes in the ileal mucosa. Conclusions: Peripheral CRH may play a proinflammatory role in toxin A–induced intestinal secretion and inflammation and that CRH1 receptor, at least in part, is important in the mediation of these responses.GASTROENTEROLOGY 2002;123:505-515

Stress and the skin

The skin is a metabolically active organ with vital functions, such as protection and homeostasis, which are threatened by any disturbance in the structural and functional integrity of the skin. To protect against stress, it has evolved a local neuroendocrine system, which utilizes common ‘stress’ peptides and receptors. Corticotropin-releasing hormone (CRH) is a 41-amino acid polypeptide that plays a major role in coordinating autonomic, cardiovascular, endocrine and behavioural responses to stress. CRH and the related urocortin peptides exert their actions by activating two different families of receptors, CRH-R1 and CRH-R2, which have a high degree of sequence homology and are expressed as multiple protein isoforms generated by differential exon splicing. The skin expresses CRH, urocortin and multiple CRH receptor subtypes.