Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01189 (beta-endorphin)
 21,003 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adaptive stress responses mediated by the endocrine, autonomic, cardiovascular and immune systems are essential for the survival of the individual. Initial stress-induced responses provide a vital short-term metabolic lift, but prolonged or inappropriate exposure to stress can compromise homeostasis thereby leading to disease. This 'fight-or-flight' response is characterized by the activation of the corticotropin-releasing hormone (CRH)-adrenocorticotropin-glucocorticoid axis, mediated by the type 1 CRH receptor. In contrast, the type 2 CRH receptor mediates the stress-coping responses during the recovery phase of stress. We identified human stresscopin (SCP) and stresscopin-related peptide (SRP) as specific ligands for the type 2 CRH receptor. The genes encoding these peptides were expressed in diverse peripheral tissues as well as in the central nervous system. Treatment with SCP or SRP suppressed food intake, delayed gastric emptying and decreased heat-induced edema. Thus SCP and SRP might represent endogenous ligands for maintaining homeostasis after stress, and could allow the design of drugs to ameliorate stress-related diseases.
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PMID:Human stresscopin and stresscopin-related peptide are selective ligands for the type 2 corticotropin-releasing hormone receptor. 1132 63

Urocortin and urocortin II are members of the corticotropin-releasing hormone (CRH) family of neuropeptides that function to regulate stress responses. Two high-affinity G-protein-coupled receptors have been identified that bind CRH and/or urocortin I and II, designated CRHR1 and CRHR2, both of which are present in hippocampal regions of mammalian brain. The hippocampus plays an important role in regulating stress responses and is a brain region in which neurons are vulnerable during disease and stress conditions, including cerebral ischemia, Alzheimer's disease, and anxiety disorders. Here we report that urocortin exerts a potent protective action in cultured rat hippocampal neurons with concentrations in the range of 0.5-5.0 pm, increasing the resistance of the cells to oxidative (amyloid beta-peptide, 4-hydroxynonenal, ferrous sulfate) and excitotoxic (glutamate) insults. We observed that urocortin is 10-fold more potent than CRH in protecting hippocampal neurons from insult, whereas urocortin II is ineffective. RT-PCR and sequencing analyses revealed the presence of both CRHR1 and CRHR2 in the hippocampal cultures, with CRHR1 being expressed at much higher levels than CRHR2. Using subtype-selective CRH receptor antagonists, we provide evidence that the neuroprotective effect of exogenously added urocortin is mediated by CRHR1. Furthermore, we provide evidence that the signaling pathway that mediates the neuroprotective effect of urocortin involves cAMP-dependent protein kinase, protein kinase C, and mitogen-activated protein kinase. This is the first demonstration of a biological activity of urocortin in hippocampal neurons, suggesting a role for the peptide in adaptive responses of hippocampal neurons to potentially lethal oxidative and excitotoxic insults.
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PMID:Urocortin, but not urocortin II, protects cultured hippocampal neurons from oxidative and excitotoxic cell death via corticotropin-releasing hormone receptor type I. 1178 85

The biological actions of corticotropin-releasing hormone (CRH) in the human myometrium during pregnancy and labor are unknown. We hypothesized that CRH may modulate the nitric oxide system, and influence myometrial relaxation/contractility. Incubation of myometrial cells with CRH, but not urocortin II or urocortin III, for 8-16 h significantly induced mRNA and protein expression of endothelial and brain but not inducible nitric oxide synthase (NOS) isoforms. This action resulted in increased activity of soluble guanylate cyclase (GC(s)), demonstrated by the enhanced cGMP-producing capacity of the NO donor, sodium nitroprusside. CRH also caused acute activation of the membrane-bound GC, shown by increased basal or atrial natriuretic peptide (ANP)-stimulated cGMP production. These effects appeared to be mediated via the R1 receptors because the CRH receptor antagonists, astressin and antalarmin but not anti-sauvagine 30, could block them. The acute effects of CRH were significantly reduced by inhibition of protein kinase A (PKA) activity, suggesting it is partially PKA dependent. Activation of protein kinase C (PKC) resulted in significant inhibition of both ANP-and CRH-stimulated cGMP production, suggesting a direct effect of PKC on membrane-bound GC. In conclusion, CRH appears to have a dual effect on myometrial NOS/GC pathway, a short term effect predominantly mediated by PKA, and a long-term effect increasing constitutive NOS expression, mediated by a PKA-independent mechanism. This mechanism could potentially be active during human pregnancy, and, because cGMP stimulates myometrial relaxation, these findings further suggest that during pregnancy CRH primarily activates intracellular signals that contribute to the maintenance of myometrial quiescence.
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PMID:Up-regulation of nitric oxide synthase and modulation of the guanylate cyclase activity by corticotropin-releasing hormone but not urocortin II or urocortin III in cultured human pregnant myometrial cells. 1185 58

The two newest members of the urocortin (UCN)/corticotropin-releasing hormone (CRH) family of peptides - UCN II and UCN III - bind to the CRH-2 receptor, suppress feeding, and are expressed in the periphery as well as the brain. We used several sensitive techniques to examine their interactions with the blood-brain barrier (BBB). Of the four known peptides in this family, each interacts with the BBB differently. UCN I barely enters the brain from blood unless its latent saturable influx system is activated by leptin or pretreatment with glucose. However, neither leptin nor glucose affected the entry of intact UCN II. UCN II reached brain paranchyma at a moderate rate that was not self-inhibited or cross-inhibited by UCN/CRH peptides. The apparent, but misleading, rapid influx of UCN III (stresscopin) could be explained by degradation at the BBB itself. Influx of CRH into brain was slower than UCN II but faster than UCN I; it was inhibited by excess CRH but not by excess UCN I, II, III, or leptin. CRH is the only member of this family to have a saturable efflux system out of the brain. Determination of hydrogen bonding, newly applied here to ingestive peptides, was not helpful in explaining these differential interactions of the UCN peptides with the BBB.
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PMID:Differential interactions of urocortin/corticotropin-releasing hormone peptides with the blood-brain barrier. 1206 89

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.
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PMID:Corticotropin releasing hormone type 2 receptors in the dorsal raphe nucleus mediate the behavioral consequences of uncontrollable stress. 1257 32

Urocortin II (Ucn II) is a novel corticotropin-releasing hormone (CRH)-related peptide discovered as a selective agonist for type-2 CRH receptor. In the rat or mouse brain, Ucn II mRNA shows weak expression mainly in the hypothalamic paraventricular nucleus (PVN) and the locus coeruleus (LC). Understanding the regulation of Ucn II mRNA expression under varying conditions provides new insights into central stress response. We examined expression of Ucn II mRNA in the PVN and LC following immobilization stress, water deprivation, and adrenalectomy. Rats subjected to immobilization stress exhibited a dramatic induction of Ucn II mRNA expression in the parvocellular part of the PVN at the end of 2 h of immobilization. In contrast, water deprivation for 3 days induced Ucn II mRNA expression mainly in the magnocellular part of the PVN. Although water-deprived rats showed a marked decrease in their food intake, pair-fed rats failed to alter PVN Ucn II mRNA expression, suggesting that osmotic stimuli per se, but not reduced food consumption during water deprivation, caused Ucn II mRNA induction in the magnocellular part of the PVN. Adrenalectomized rats failed to show an increase in Ucn II mRNA in the PVN when compared to sham-operated rats. Double-label in situ hybridization revealed colocalization of Ucn II mRNA in approximately 45% of the CRH mRNA-expressing cells in the parvocellular part of the PVN following immobilization, or colocalization in most of the vasopressin mRNA-expressing cells in the magnocellular part of the PVN following water deprivation. In the LC, no induction of Ucn II mRNA was observed in any of the three experimental conditions, indicating that the regulation of Ucn II mRNA expression was site-specific. The results show a stressor-specific regulation of Ucn II mRNA expression in the PVN and raise the possibility that Ucn II mRNA plays a modulatory role in stress-induced alteration of anterior and posterior pituitary function, depending on the type of stress.
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PMID:Effect of stress and adrenalectomy on urocortin II mRNA expression in the hypothalamic paraventricular nucleus of the rat. 1286 94

Urocortin (UCN), a member of the Corticotropin-Releasing Factor (CRF) family of peptides is a well described cardioprotective agent. UCN is able to bind to two types of G-protein coupled receptors: CRF receptor type 1 (CRFR1) and CRF receptor type 2 (CRFR2), whereas, two homologues of UCN, stresscopin (SCP) or also known as urocortin III (UCNIII) and stresscopin related peptide (SRP), or urocortin II (UCNII), bind exclusively and with high affinity to CRFR2, we hypothesised that they will exhibit more pronounced cardioprotective effects than UCN. We show for the first time that SCP is expressed in rat cardiomyocytes and that the levels of SRP and SCP are increased by hypoxic stress. All three peptides have potent cardioprotective effects in cells exposed to hypoxia/reoxygenation. When used at 10(-8) M they increased the amount of live cells by 25% when added prior to hypoxia, and by 20% when UCN and SCP were added at the onset of reoxygenation. In addition, the peptides are equally are more potent antiapoptotic factors than UCN. The antiapoptotic effects of SCP were more pronounced than SRP and UCN at a concentration of 10(-10) M. Furthermore, SCP and SRP protect cardiomyocytes better than UCN at concentrations up to and including 10(-10) M and reduced the amount of TUNEL positive cells almost by half at concentrations of 10(-12) to 10(-10) M. More importantly, we demonstrate that SCP and SRP are able to protect cardiomyocytes even if they are administered after the hypoxic insult and prior to reoxygenation. In this case SCP was more potent than UCN and SRP at 10(-12) M and both SCP and SRP exhibited higher protection at 10(-8) M compared to UCN. Cardioprotection of cardiomyocytes by 10(-8) M of peptides was abolished when treated with 50 microM LY294002 or 100 microM PD98059, but not by 10 microM SB203580 prior to the hypoxic insult. Transfection of dominant negative Akt and MEK1 also blocked protection by the peptides, whereas dominant negative MEKK6 had no effects, demonstrating that SCP and SRP, like UCN, require activation of p42/44 Mitogen activated protein kinase and Akt/Protein Kinase B in order to produce their cardioprotective effects. In addition, we showed that SCP and UCN are potent activators of the p42/44 MAPK pathway, with SRP able to induce phosphorylation of p42/44 MAPK as well, albeit not as pronounced.
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PMID:Protective effects of the urocortin homologues stresscopin (SCP) and stresscopin-related peptide (SRP) against hypoxia/reoxygenation injury in rat neonatal cardiomyocytes. 1451 39

The behavioral consequences of uncontrollable stress that are collectively called learned helplessness (LH) are mediated in part by increased levels of serotonin (5-HT) activity in the dorsal raphe nucleus (DRN) and it's projection regions. Recently, corticotropin-releasing hormone (CRH) within the DRN has been implicated in the development of LH because intra-DRN CRH produces LH at very high doses, and because intra-DRN antagonists for the CRH 2 receptor (CRHR2) block LH. Since these behavioral effects are mediated by both 5-HT excitation and CRHR2 activation, we have suggested that CRHR2 mediates excitation of DRN 5-HT neurons. However, CRH has been shown to inhibit DRN 5-HT neurons at low doses that are expected to bind to CRHR1. Since CRHR1 antagonists were ineffective in blocking LH, we have further suggested that CRHR1 might mediate the inhibition of DRN 5-HT neurons. In support of this hypothesis, although low doses of CRH that preferentially bind CRHR1 inhibit DRN 5-HT activity, higher doses at which CRH would be expected to bind both receptor subtypes no longer inhibit DRN 5-HT. In addition, high doses of CRH are required to produce LH, which is known to be mediated by 5-HT excitation, and the CRHR2 agonist urocortin II (UCN II) produces LH at much lower doses than does CRH. The present studies show that intra-DRN CRH microinjection blocks the behavioral effects produced by DRN UCN II, but only at doses that have been shown to inhibit DRN 5-HT activity. Indeed, a higher dose of CRH that has been shown to no longer inhibit DRN 5-HT activity did not affect the behavioral consequences of DRN UCN II. In a separate experiment, the effective dose of CRH blocked the usual behavioral consequences of uncontrollable stress.
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PMID:Low doses of corticotropin-releasing hormone injected into the dorsal raphe nucleus block the behavioral consequences of uncontrollable stress. 1465 70

Corticotropin releasing factor 2 receptor selective analogs of the amphibian peptide sauvagine, a member of the corticotropin releasing factor (CRF) peptide family, have therapeutic potential for the treatment of skeletal muscle atrophy. Previously, we demonstrated that [P11X12X13]Svg peptides have improved CRF2R selectivity, although not to the level of CRF2R selective hormones such as urocortin 2 and urocortin 3. Since we also demonstrated a potential for improvement in selectivity of sauvagine by modifications of residues 35 and 39, we investigated substitutions of these amino acids in selected [P11X12X13]Svg peptides. We have observed that substitution of Arg35 in sauvagine to Ala35 (the amino acid found in all CRF2R selective agonists), increased the selectivity of [P11, X12, X13]Svg analogs. In contrast, substitution of Asp39 in sauvagine to Ala39 (also the amino acid found in all CRF2R selective agonists) did not further increase the selectivity of [P11, X12, X13, A35]Svg analogs. Thus, the residues 35 along with 11, 12, and 13 in sauvagine represent important sites for improving CRF2R selectivity.
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PMID:Sauvagine analogs selective for corticotropin releasing factor 2 receptor: effect of substitutions at positions 35 and 39 on CRF2R selectivity. 1580 19

Urocortin (Ucn) II and III, homologous peptides of Ucn that are specific ligands for corticotropin-releasing hormone (CRH) type 2 receptor (CRH-R2), have recently been identified. The present study was designed to elucidate the effects of Ucn II, which is predominantly expressed in rodent heart, on neonatal rat cardiac myocytes (MCs) and cardiac non-myocytes (NMCs). Ucn II increased the incorporation of [3H]-leucine into MCs, as well as the accumulation of cAMP and the secretion of atrial natriuretic peptide. However, no significant changes were demonstrated in NMCs or an MC/NMC co-culture system. The effects of Ucn II were attenuated by astressin2-B, a specific antagonist of CRH-R2, and/or H89, an inhibitor of protein kinase A (PKA). These results indicate that Ucn II may be another endogenous cardiovascular substance that acts via CRH-R2 and the cAMP-dependent PKA pathway.
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PMID:Effects of urocortin II on neonatal rat cardiac myocytes and non-myocytes. 1600 43


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