Urocortin (human)

Urocortin 1 expression and secretion by human umbilical vein endothelial cells: In vitro effects of interleukin 8, interferon gamma, lipopolysaccharide, endothelin 1, prostaglandin F-2alpha, estradiol, progesterone and dexamethasone.[Pubmed:26549126]

Peptides. 2015 Dec;74:64-9.

Urocortin 1 (Ucn1) is a 40-amino-acid peptide that has vasodilatory activity and displays immunomodulatory and antioxidant properties. Maternal and cord plasma Ucn1 levels are increased in preeclampsia and preterm labor, but the mechanisms of such increase are poorly known. Thus, we investigated Ucn1 localization in human umbilical cord and assessed some potential stimuli to Ucn1 release by human umbilical vein endothelial cells (HUVEC). Human umbilical cords were obtained at uncomplicated term pregnancy (n=11). Ucn1 localization was assessed by immunohistochemistry and quantified. HUVEC were grown in vitro to confluence, then incubated with serial concentrations of interleukin (IL)-8, interferon (INF)-gamma, lipopolysaccharide (LPS), endothelin (ET)-1, prostaglandin (PG)F-2alpha, estradiol, progesterone and dexamethasone and Ucn1 concentrations were measured in the supernatants. Ucn1 was immunolocalized with similar intensity in umbilical cord arteries, vein and Wharton's jelly. Ucn1 mRNA was detected in all HUVEC cultures and Ucn1 peptide was detectable in culture medium from untreated cells at different time points. Incubation with IFN-gamma increased Ucn1 secretion in a dose-dependent manner. Treatments with IL-8, LPS, ET-1 and dexamethasone were able to increase three to fourfold Ucn1 release from cultured endothelial cells. In conclusion, umbilical vessels express Ucn1 and may be a contributive source of Ucn1 release into fetal-placental circulation. IL-8, IFN-gamma, LPS, ET-1 and dexamethasone promote Ucn1 secretion from cultured HUVEC.

Human muscle sympathetic nerve responses to urocortin-2 in health and stable heart failure.[Pubmed:26173485]

Clin Exp Pharmacol Physiol. 2015 Sep;42(9):888-895.

Sympatholytic and vasodilator drugs have been of major therapeutic benefit in patients with heart failure (HF). Urocortin-2 (Ucn2) is a small corticotrophin-related peptide distributed throughout the cardiovascular system which inhibits cardiac sympathetic nerve activity (CSNA) and is also a powerful vasodilator. This study analysed the effects of a 60-min infusion of Ucn2 (25 mug) on muscle sympathetic nerve activity (MSNA) recorded from the lower limb in eight healthy men and four men with stable HF. During Ucn2 infusion, mean arterial pressure fell to a nadir of 84 +/- 2 compared to 95 +/- 2 mmHg during placebo (P = 0.001) and heart rate increased to a maximum of 74 +/- 1 compared to 64 +/- 1 b.p.m. (P < 0.001). Total peripheral resistance fell by 23 +/- 4% compared with an increase of 23 +/- 4% (P < 0.001) and cardiac output increased by 22 +/- 4 compared to 4 +/- 4% (P = 0.001). The MSNA burst frequency increased by 9 +/- 2 compared to 1 +/- 2 burst/min (P = 0.005) and burst area/min by 133 +/- 7 vs 107 +/- 7% (P = 0.01). Burst incidence and baroreflex sensitivity were not significantly altered. Qualitatively similar changes were observed in stable HF patients. Ucn2-induced vasodilatation increased MSNA in humans, as opposed to the decrease in CSNA we observed in sheep. Therefore, if Ucn2 has a central inhibitory effect on MSNA, it was over-run by off-loading the cardiovagal baroreflex. Alternatively, CSNA may be less responsive to baroreflex off-loading than MSNA.

Second-trimester amniotic fluid corticotropin-releasing hormone and urocortin in relation to maternal stress and fetal growth in human pregnancy.[Pubmed:28347187]

Stress. 2017 May;20(3):231-240.

This study explored the association between the acute psychobiological stress response, chronic social overload and amniotic fluid corticotropin-releasing hormone (CRH) and urocortin (UCN) in 34 healthy, second-trimester pregnant women undergoing amniocentesis. The study further examined the predictive value of second-trimester amniotic fluid CRH and UCN for fetal growth and neonatal birth outcome. The amniocentesis served as a naturalistic stressor, during which maternal state anxiety and salivary cortisol was measured repeatedly and an aliquot of amniotic fluid was collected. The pregnant women additionally completed a questionnaire on chronic social overload. Fetal growth parameters were obtained at amniocentesis using fetal ultrasound biometry and at birth from medical records. The statistical analyzes revealed that the acute maternal psychobiological stress response was unassociated with the amniotic fluid peptides, but that maternal chronic overload and amniotic CRH were positively correlated. Moreover, amniotic CRH was negatively associated with fetal size at amniocentesis and positively with growth in size from amniocentesis to birth. Hardly any studies have previously explored whether acute maternal psychological stress influences fetoplacental CRH or UCN levels significantly. Our findings suggest that (i) chronic, but not acute maternal stress may affect fetoplacental CRH secretion and that (ii) CRH is complexly involved in fetal growth processes as previously shown in animals.

Antiamnesic properties of analogs and mimetics of the tripeptide human urocortin 3.[Pubmed:27262310]

Amino Acids. 2016 Sep;48(9):2261-6.

Amnesia is a deficit in memory caused by brain damage, disease, or trauma. Until now, there are no successful medications on the drug market available to treat amnesia. Short analogs and mimetics of human urocortin 3 (Ucn 3) tripeptide were synthetized and tested for their action against amnesia induced by eletroconvulsion in mice. Among the 16 investigated derivatives of Ucn 3 tripeptide, eight compounds displayed antiamnesic effect. Our results proved that the configuration of chiral center of glutamine does not affect the antiamnesic properties. Alkyl amide or isoleucyl amide at the C-terminus may lead to antiamnesic compounds. As concerned the N-terminus, acetyl, Boc, and alkyl ureido moieties were found among the active analogs, but the free amino function at the N-terminus usually led to an inactive derivatives. These observations may lead to the design and synthesis of small peptidomimetics and amino acid derivatives as antiamnesic drug candidates, although the elucidation of the mechanism of the action requires further investigations.

Corticotropin-releasing factor receptors 1 and 2 in anxiety and depression.[Pubmed:11786305]

Curr Opin Pharmacol. 2002 Feb;2(1):23-33.

Corticotropin-releasing factor (CRF) and its related family members are implicated in stress-related disorders such as anxiety and depression. Recently, two new members of this neuropeptide family have been discovered in the brain: urocortin II (also known as stresscopin-related peptide) and urocortin III (also known as stresscopin). These urocortins are selective agonists for the CRF(2) receptor, show a distinct neuroanatomical localization and are involved in stress-coping responses such as anxiolysis. Thus, CRF, the urocortins and their receptors form an intricate network in the brain involved in the acute phase as well as the recovery phase of the stress response.

The neurobiology of urocortin.[Pubmed:11033056]

Regul Pept. 2000 Sep 25;93(1-3):85-92.

Urocortin (UCN) is a recently isolated 40 amino acid-containing neuropeptide that is the second endogenous mammalian ligand for the corticotropin-releasing factor (CRF) receptors. While UCN and CRF both display a similar high affinity for the CRF(1) receptor, the affinity of UCN for the CRF(2) receptor is more than 10-fold higher than that of rat/human CRF. UCN mRNA expression is highest in the Edinger-Westphal nucleus and lateral superior olive, with the most prominent terminal fields found in the lateral septum. Because of the higher relative affinity of UCN for the CRF(2) receptor and the corresponding neuroanatomical distribution of the highest density of UCN expression and innervation to brain regions preferentially expressing the CRF(2) receptor subtype, it has been hypothesized that UCN is the preferred endogenous ligand for the CRF(2) receptor. Following central administration, UCN has been demonstrated to produce behavioral and physiological effects that are qualitatively similar to CRF. Quantitatively, however, UCN appears to be a more potent suppressor of ingestive behavior (food and water intake) and a less potent inducer of anxiogenic behavior than CRF.

Corticotropin releasing factor receptors and their ligand family.[Pubmed:10816663]

Ann N Y Acad Sci. 1999 Oct 20;885:312-28.

The CRF receptors belong to the VIP/GRF/PTH family of G-protein coupled receptors whose actions are mediated through activation of adenylate cyclase. Two CRF receptors, encoded by distinct genes, CRF-R1 and CRF-R2, and that can exist in two alternatively spliced forms, have been cloned. The type-1 receptor is expressed in many areas of the rodent brain, as well as in the pituitary, gonads, and skin. In the rodent, one splice variant of the type-2 receptor, CRF-R2 alpha, is expressed mainly in the brain, whereas the other variant, CRF-R2 beta, is found not only in the CNS, but also in cardiac and skeletal muscle, epididymis, and the gastrointestinal tract. The poor correlation between the sites of expression of CRF-R2 and CRF, as well as the relatively low affinity of CRF for CRF-R2, suggested the presence of another ligand, whose existence was confirmed in our cloning of urocortin. This CRF-like peptide is found not only in brain, but also in peripheral sites, such as lymphocytes. The broad tissue distribution of CRF receptors and their ligands underscores the important role of this system in maintenance of homeostasis. Functional studies of the two receptor types reveal differences in the specificity for CRF and related ligands. On the basis of its greater affinity for urocortin, in comparison with CRF, as well as its brain distribution, CRF-R2 may be the cognate receptor for urocortin. Mutagenesis studies of CRF receptors directed toward understanding the basis for their specificity, provide insight into the structural determinants for hormone-receptor recognition and signal transduction.

Urocortin, human, a 40-aa neuropeptide, acts as a selective agonist of endogenous CRF2 receptor, with Kis of 0.4, 0.3, and 0.5 nM for hCRF1, rCRF2α and mCRF2β, respectively.

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