UNIPROT:P01189 - FACTA Search

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Query: UNIPROT:P01189 (beta-endorphin)
21,003 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Corticotropin releasing factor (CRF)-stimulated adenylate cyclase activity and receptor binding were examined in rat brain homogenates using a potent synthetic CRF analog--[D-Tyr3,D-Pro4,Nle18,21,alpha-helical]CRF3-41 (alpha-hel CRF3-41). Binding of alpha-hel CRF3-41 in the rat brain was saturable, reversible, of high affinity and exhibited relevant peptide specificity. This analog also stimulated adenylate cyclase activity of various brain regions; the greatest magnitude of stimulation was in the cerebral cortex followed by the septum, cerebellum and thalamus. Adenylate cyclase stimulation in the cerebral cortex was concentration-dependent with an ED50 of 2.5 +/- 0.4 nM for alpha-hel CRF3-41 and an ED50 of 16 +/- 2 nM for ovine and rat CRF. Maximal stimulation was comparable for all peptides. Agonist-stimulated adenylate cyclase activity was competitively blocked by the CRF antagonists. The inactive CRF analog, ovine CRF1-39, at concentrations less than 1 microM, did not significantly stimulate adenylate cyclase. Adrenalectomy, which has been reported to modulate CRF receptor number and CRF-stimulated adenylate cyclase activity in the anterior pituitary, had no effect on CRF receptor binding or CRF-stimulated adenylate cyclase activity in the cerebral cortex. These results suggest that, as in the anterior pituitary, at least some of the physiological responses mediated by CRF receptors in the brain utilize the cyclic nucleotide regulatory pathway as a post-receptor mechanism.
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PMID:Corticotropin releasing factor receptor-mediated stimulation of adenylate cyclase activity in the rat brain. 301 76

Corticotropin-releasing factor (CRF) acts on at least two types of CRF receptors. To search for selective CRF receptor agonists, 37 ovine CRF analogs, systematically substituted with D-amino acids, were tested for inhibitory activity on edema induced in the pentobarbital-anesthetized rat paw by heat (immersion in 58 degrees C water for 1 min). The activity of each analog, administered 21 nmol/kg i.v. 10 min before heat, was compared to published data on the analog's potency in stimulating adrenocorticotropin (ACTH) release from cultured rat pituitary cells. In general, a positive rank correlation was found between the anti-edema and neuroendocrine activities of these analogs, however, one outlier, [D-Pro5]ovine CRF, exhibited greater selectivity for anti-edema activity. The human/rat analog of [D-Pro5]CRF was synthesized and found to be equipotent to human/rat CRF for suppression of heat-edema. In cells transfected with two types of cloned CRF receptors, the intracellular cAMP response to [D-Pro5]human/rat CRF was equipotent to human/rat CRF in the heart-muscle CRF (CRF2 beta) receptor assay but was five times less potent than human/rat CRF in the pituitary-central nervous system CRF (CRF1) receptor assay. We conclude that changing residue Pro5 in the CRF molecule from a L- to a D-configuration confers selectivity by decreasing second messenger activation at the CRF1 receptor whilst retaining full potency at the CRF2 beta receptor.
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PMID:[D-Pro5]Corticotropin-releasing factor analogs as selective agonists at corticotropin-releasing factor receptors. 881 28

The ability to respond to adverse environmental cues is present in the neonatal and infant rat, although in an immature form: A number of laboratories have demonstrated stress-induced elevations of plasma glucocorticoids during the first two postnatal weeks. The limbic and hypothalamic mechanisms controlling the hormonal stress-response during this period are not fully understood and are, therefore, the focus of this report. Both hypothalamic corticotropin-releasing hormone (CRH) and vasopressin contribute to the release of ACTH from the pituitary in the adult. The relative roles of these two peptides during the neonatal (first week) and infant (second week) developmental period, are controversial. Evidence is presented that argues strongly for a major role for CRH. Up-regulation of hypothalamic CRH synthesis is a major component in the mature stress response. CRH-mRNA levels in the hypothalamic PVN are increased with cold stress by ninth postnatal day, but not during the first postnatal week. Further, down-regulation of CRH gene expression by glucocorticoids (GC) constitutes a critical "shut-down" mechanism for the hormonal stress response. In vivo and in vitro experiments supporting the "immaturity" of GC feedback on CRH synthesis during the first postnatal week are described. CRH-mediated neurotransmission, in both the endocrine and neuronal effector arms of the response to stress may be modulated via alteration of receptor number. The first member of the CRH receptor family, CRF1, probably mediates the neuroendocrine effects of CRH. The developmental profile of CRF1-mRNA reveals several distinctive spatial and temporal patterns. In the hippocampal CA1, CA2, and CA3a peak (300-600% adult values) CRF1-mRNA is found on postnatal day 6. In the amygdala, CRH receptor mRNA levels are maximal on the ninth postnatal day (at 180% of adult values). In cortex, a steady decline from high postnatal day 2 levels results in adult levels by 12. These findings demonstrate distinct, regional, age-specific control of the synthesis of CRF1. Receptor expression profile may provide important information regarding modulation of the age-specific roles of CRH in different regions. For example, a high ratio of hippocampus/amygdala receptors may preferentially activate negative hippocampal input to the hypothalamus during the neonatal period. Additionally, increased CRH receptor mRNA in the infant compared with the adult provides a mechanism for enhanced excitatory effect of the peptide at this age. In conclusion, increasing evidence exists for multiple control points of the early postnatal response and adaptation to stress. CRH synthesis in hypothalamus and amygdala, its sensitivity to GC feedback, and the abundance and distribution of at least two distinct CRH receptors in the limbic central nervous system and the pituitary are developmentally regulated. All serve as control points permitting an effective endocrine, autonomic, and behavioral response to stressful environmental cues.
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PMID:Development neurobiology of the stress response: multilevel regulation of corticotropin-releasing hormone function. 916 Sep 75

The purpose of the present study is to determine the distribution of CRF containing afferents, and correlate these findings with the distribution of CRF binding sites and the neuronal localization of mRNA for the CRF1 receptor in the cerebellum of a single species, the mouse. Corticotropin releasing factor (CRF) has been localized within climbing fibers and mossy fibers throughout the cerebellar cortex of the mouse using immunohistochemistry. CRF immunoreactive, axonal varicosities also are present within all four of the cerebellar nuclei. 125I-labeled CRF binding sites are evident throughout all three layers of the cerebellar cortex (molecular, Purkinje and granule cell layers), but are not seen within the cerebellar nuclei. In situ hybridization histochemistry was employed using an antisense riboprobe corresponding to the full length sequence of the rat mRNA for the CRF1 receptor. Positive signal is present throughout the cerebellum in Purkinje cells and the granule cell layer. CRF1 receptor mRNA also is expressed within all four of the cerebellar nuclei. Further experiments are required to reconcile the lack of CRF binding sites in the cerebellar nuclei with the positive mRNA receptor expression and the presence of immunoreactive axonal varicosities. In previous physiological experiments, iontophoretic application of CRF enhances spontaneous as well as quisqualate-induced activity of Purkinje cells in slice preparations of the mouse cerebellum. When the results of the anatomical techniques are compared to the physiological data, there is convergent evidence to suggest that CRF influences the firing rate or responsiveness of Purkinje cells directly via release of the peptide from the climbing fiber system and indirectly via the mossy fiber-granule cell-parallel fiber circuit. Taken together, these anatomical and physiological data provide strong evidence to suggest that, in the adult cerebellum, CRF functions as a neuromodulator.
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PMID:The distribution of corticotropin-releasing factor (CRF), CRF binding sites and CRF1 receptor mRNA in the mouse cerebellum. 919 38

Corticotropin releasing factor (CRF) is the key coordinator of the neuroendocrine and behavioral responses to stress. In the central nervous system, CRF excites select neuronal populations, and infusion of CRF into the cerebral ventricles of infant rats produces severe age-dependent limbic seizures. These seizures, like other CRF effects, result from activation of specific receptors. Both of the characterized members of the CRF receptor family (CRF1 and CRF2), are found in the amygdala, site of origin of CRF-induced seizures, and may therefore mediate these seizures. To determine which receptor is responsible for the excitatory effects of CRF on limbic neurons, a selective, non-peptide CRF1 antagonist was tested for its ability to abolish the seizures, in comparison to non-selective inhibitory analogues of CRF. Pretreatment with the selective CRF1 blocker (NBI 27914) increased the latency and decreased the duration of CRF-induced seizures in a dose-dependent manner. The higher doses of NBI 27914 blocked the behavioral seizures and prevented epileptic discharges in concurrent electroencephalograms recorded from the amygdala. The selective CRF1 blocker was poorly effective when given systemically, consistent with limited blood-brain barrier penetration. Urocortin, a novel peptide activating both types of CRF receptors in vitro, but with preferential affinity for CRF2 receptors in vivo, produced seizures with a lower potency than CRF. These limbic seizures, indistinguishable from those induced by CRF, were abolished by pretreatment with NBI 27914, consistent with their dependence on CRF1 activation. In summary, CRF induces limbic seizures in the immature rat, which are abolished by selective blocking of the CRF1 receptor. CRF1-messenger RNA levels are maximal in sites of seizure origin and propagation during the age when CRF is most potent as a convulsant. Taken together, these facts strongly support the role of the developmentally regulated CRF1 receptor in mediating the convulsant effects of CRF in the developing brain.
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PMID:The CRF1 receptor mediates the excitatory actions of corticotropin releasing factor (CRF) in the developing rat brain: in vivo evidence using a novel, selective, non-peptide CRF receptor antagonist. 937 7

Corticotropin releasing factor (CRF) activates two known receptor types, CRF1, and CRF2. In the adult rat brain, CRF2 has a distinct distribution pattern, suggesting that it may mediate functions exclusive of CRF1. The goal of this study was to determine the age-dependent distribution of CRF2-messenger RNA (CRF2-mRNA) in the rat brain. Brains from rats sacrificed under stress-free conditions on fetal days (F) 15, 16, 17 and 19, and postnatal days 1, 3, 5, 7, 9, 12, 15, 25, 49, and 90 (adult) were analyzed using semiquantitative in situ hybridization histochemistry. The onset and distribution of CRF2-mRNA in the developing rat brain revealed important differences from the adult expression pattern: earliest expression of CRF2-mRNA was observed in the ventromedial hypothalamus (VMH) on F16. High levels of CRF2-mRNA were present in the fronto-parietal cortex in the fetal and early postnatal brain but not later. Conversely, no CRF2-mRNA was detectable in the ventroposterior (lateral and medial) thalamic nuclei prior to postnatal day 7. Distinct developmental profiles of CRF2-mRNA were also observed in the lateral septum, medial, basal and cortical amygdala nuclei, and in several hippocampal fields. In conclusion, CRF2 is expressed in the hypothalamus on F16, prior to the detection of CRF itself in the paraventricular nucleus. The differential levels and distributions of CRF2-mRNA in hypothalamic and limbic brain regions indicate a precise regulation of this receptor's expression during development, as shown for CRF1. Regulation of the levels of CRF2 may modulate the effects of CRF (and related ligands) on target neurons, consistent with differential maturation of the functions mediated by this receptor.
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PMID:The developmental profile of the corticotropin releasing factor receptor (CRF2) in rat brain predicts distinct age-specific functions. 960 71

Human neutrophils in whole blood become bipolar in shape after exposure to chemokinetic stimuli. In normal blood, the proportion of non-spherical neutrophils was 1.2 +/- 0.07% (n = 101). After incubation of blood samples with corticotropin-releasing hormone (CRF, 1 to 20 microM) 36 of 101 subjects exhibited a > or = 10% bipolar-shape ellipsoid response. This ellipsoid response was more frequent in female than in male subjects (32/75 vs. 4/26, p < 0.01). Female Caucasian subjects were more sensitive to CRF than female East Asian subjects (25/48 vs. 2/15, p < 0.01). Age was not a factor in sensitivity to CRF. In young female East Asian subjects (23 +/- 0.4 years, n = 8) that did not manifest the ellipsoid response to CRF, formyl-Met-Leu-Phe (fMLP), a chemotactic peptide, 10(-9) M increased non-spherical neutrophils to 31 +/- 0.8%. In these individuals, the fMLP response was inhibited in a dose-dependent manner by CRF. The pharmacological profile of the stimulatory and fMLP-inhibitory actions of CRF on neutrophil shape was consistent with that of a CRF1-receptor mediated response. Expression of mRNA for the CRF1-receptor was detected in hematopoietic cell lines (e.g., HL-60) using a reverse transcriptase polymerase chain-reaction method. The bipolar-shape response of human neutrophils to CRF has the potential to be a useful indicator of the functional state of this hormone-receptor system in inflammation.
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PMID:Bipolar-shape response of human neutrophils to corticotropin-releasing factor. 967 Nov 11

Corticotropin releasing factor (CRF) is the major neuropeptide regulating the hypothalamo-pituitary-adrenocortical axis in most species. A pituitary receptor for CRF (designated CRF1) belonging to the seven-transmembrane helix, G-protein-coupled receptor superfamily has been cloned for human, rat, mouse and xenopus. Since ovine CRF shares only 84% identity to human/rat CRF (h/rCRF) we postulated that the sheep pituitary CRF1 receptor may have similarly diverged from the rodent and human CRF1. We report the molecular cloning of an ovine pituitary cDNA containing a 1245 bp open reading frame encoding a 415 amino acid sheep CRF1 receptor 78, 86, 94, and 95% homologous to xenopus, chicken, rat, mouse, and human CRF1, respectively. The divergence in primary structure between the sheep CRF1 and the other mammalian CRF1s is primarily localized to the extracellular amino terminal domain of the receptor (18 of 22 divergent residues, ovine vs human CRF1). A variant of the oCRF1 was also isolated (oCRF1var) with 133 bp deleted from nucleotide (nt) 1080 to nt 1213 of the open reading frame (ORF) resulting in a new ORF of 1176 nt predicting a 392 residue CRF1 variant receptor. The 133 bp deletion would cause a frame-shift at residue 358 within the carboxyl-third of the seventh transmembrane domain (TM7) resulting in a shortened cytoplasmic tail with a new amino acid sequence from residue 358 to 392. Scatchard analysis of saturation curves using membrane prepared from Cos 7 cells transfected with oCRF1 or oCRF1var indicated that both wild-type and variant receptors were expressed similarly (number of CRF binding sites) and both bound oCRF with high affinity [oCRF1 (Kd): 2.5 + 1.6 nM; oCRF1var: 5.1 + 2.3 nM]. The non-hydrolyzable GTP analogue (GTPgammaS) lowered the affinity of both wild-type and variant oCRF1 receptors to a similar extent (oCRF1: 18.2 nM; oCRF1var: 22.4 nM). Both wild-type and variant oCRF1 receptors exhibited approximately 10-fold greater selectivity for oCRF and sauvagine compared to h/rCRF or alpha-helical [9-41]oCRF. CRF effectively stimulated the accumulation of cAMP (EC50 = 51 pM) in Cos 7 cells transiently transfected with wild-type but not variant oCRF1 receptor. In Cos 7 cells transfected with oCRF1var, cAMP accumulation was only observed at the highest concentration of oCRF utilized (100 nM). Basal (unstimulated) levels of cAMP in Cos 7 cells transfected with oCRF1var (in the presence of 2 mM IBMX) were approximately 50% lower than for the wild-type oCRF1. Differences in cAMP accumulation could not be attributed to differences in receptor number since total binding sites in the transfected cells were not different between wild-type or variant oCRF1 receptors. Agonist-induced receptor internalization, determined as the percent of total [125I] Tyr0-oCRF bound located in the acid-resistant fraction of transfected Cos 7 cells, increased with time (0-60 min at 37 degrees C) for both wild-type and variant oCRF1. Wild-type CRF1 internalized approximately 2-fold greater percent of total [125I] Tyr0-oCRF bound compared to the variant receptor. In summary, an ovine CRF1 and a CRF1 cytoplasmic tail receptor variant displaying high affinity binding to oCRF as well as selectivity for oCRF vs h/rCRF, were cloned from an adult sheep pituitary cDNA library. GTPgammaS studies indicate that both variant and wild-type receptors couple efficiently to Galphas however, only the wild-type oCRF1 is capable of stimulating cAMP production at physiological levels of CRF. Agonist-induced internalization of the ovine CRF1var is also reduced compared to the wild-type CRF1 receptor. We suggest that the oCRF1var interacts efficiently with Galphas but is unable (post-hormonal binding) to effectively stimulate G-protein activation of adenylate cyclase, indicating that the cytoplasmic tail of the CRF1 can modulate receptor function related to signal transduction. (ABSTRACT TRUNCATED)
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PMID:Structure and function of the ovine type 1 corticotropin releasing factor receptor (CRF1) and a carboxyl-terminal variant. 986 24

As described in the preceding paper (Arvanitis et al. J. Med. Chem. 1999, 42), anilinopyrimidines I were identified as potent antagonists of corticotropin-releasing hormone-1 receptor (CRH1-R, also referred to as corticotropin-releasing factor, CRF1-R). Our next goal was to understand the receptor-bound conformation of the antagonists and to use this information to help guide preclinical optimization of the series and to develop new leads. Since receptor structural information was not available, we assumed that these small, high-affinity antagonists would tend to bind in conformations at or energetically close to their global minima and that rigid analogues that maintained the important stereoelectronic features of the bound anilinopyrimidine would also bind tightly. Conformational preferences and barriers to rotation of the anilinopyrimidines were determined by semiempirical methods, and X-ray and variable-temperature NMR spectroscopy provided experimental results that correlated well with calculated structures. Using these data, a key dihedral angle was constrained to design fused-ring analogues, substituted N-arylpyrrolopyridines II, synthesis of which provided CRH1 receptor antagonists with potency equal to that of the initial congeneric leads (Ki = 1 nM) and which closely matched the conformation held by the original compound, as determined by crystallography. In addition to providing a useful template for further analogue synthesis, the study unequivocally determined the active conformation of the anilinopyrimidines. Theoretical and spectroscopic studies, synthesis, and receptor binding data are presented.
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PMID:Corticotropin-releasing hormone receptor antagonists: framework design and synthesis guided by ligand conformational studies. 1007 80

A novel series of derivatives of oxo-7H-benzo[e]perimidine-4-carboxylic acid (I) potently displaced radioligand binding of 125I-CRF to both CRF1 and CRF2 receptors. The members of this series antagonized CRF-stimulated cAMP formation and CRF-stimulated corticotropin release from rat pituitary in vivo. These are the first nonpeptide antagonists to show activity at both CRF1 and CRF2 receptors.
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PMID:Synthesis and biological activity of oxo-7H-benzo[e]perimidine-4-carboxylic acid derivatives as potent, nonpeptide corticotropin releasing factor (CRF) receptor antagonists. 1020 44

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