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)

Human HEK293 cells that stably express the Epstein Barr nuclear antigen 1 (EBNA1) support the episomal replication of plasmids containing the Epstein Barr virus origin of replication (EBV oriP). A 293EBNA (293E) cell line expressing the human corticotropin-releasing hormone receptor subtype I (CRHR1) from an episomal plasmid was generated (293CR1s), analyzed, adapted to spinner culture, and scaled-up for production in less than 6 weeks. Forty-seven stable CHO cell lines transfected with CRHR1 were also isolated. Expression of the receptor in the best of these lines (as judged by CRH-induced cAMP production), CHO-R22, was compared to that in 293CR1s cells. Results indicate that the CRHR1 episomal expression vector in 293E cells (1) rapidly generates stable cell lines suitable for scale-up; (2) is stably maintained during 3 months in culture; (3) expresses high levels of CRHR1 mRNA; and (4) expresses significantly more CRHR1 than the CHO-R22 line. Coexpression of additional G protein alpha subunit (G alpha s) with CRHR1 in 293E cells converts a higher percentage of receptor to the agonist high-affinity G-protein-coupled state. Our data support the idea that using the EBV oriP-driven episomal system for gene expression results in greater production of protein in a relatively short period of time.
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PMID:Rapid generation of stable cell lines expressing corticotropin-releasing hormone receptor for drug discovery. 912

Novel corticotropin-releasing hormone receptor (CRHR), designated type-2alpha CRHR (CRHR-2alpha), was recently cloned and functionally characterized. In situ hybridization study revealed that CRHR-2alpha mRNA had a distinct distribution from type-1 CRHR (CRHR-1) mRNA in the rat brain. Interestingly, CRHR-2alpha mRNA showed a relatively high expression in the hypothalamic paraventricular nucleus (PVN) even under unstressful condition. This may reflect the important role of CRHR-2alpha in the autoregulation of CRH secretion in the PVN. To determine the regulation of CRHR-2alpha mRNA expression in the PVN, we examined the alteration of CRHR-2alpha mRNA levels in the PVN in rats with lipopolysaccharide (LPS) injection, corticosterone (CORT) administration or adrenalectomy and compared with that of CRHR-1 mRNA, using in situ hybridization histochemistry. I.p. LPS injection (50 microg) induced a significant increase in PVN CRHR-1 mRNA at 3 and 6 h whereas CORT administration (10 mg/day for 12 days) or adrenalectomy (sacrificed 7 days after surgery) decreased CRHR-1 mRNA levels in the PVN. These alterations in PVN CRHR-1 mRNA are consistent with previous reports. In contrast, CRHR-2alpha mRNA levels in the PVN were not altered by any of these treatments. These results indicate that CRHR-1 and CRHR-2alpha mRNA are differentially regulated in the PVN. Further study will be necessary to elucidate the CRHR-2alpha function in the PVN.
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PMID:Differential regulation of type-1 and type-2alpha corticotropin-releasing hormone receptor mRNA in the hypothalamic paraventricular nucleus of the rat. 922 14

We tested the effect of endotoxin on the peripheral corticotropin-releasing hormone receptor (CRH-R2), which is highly expressed in the heart. Systemic injection of LPS markedly downregulated CRH-R2 mRNA levels in the heart in a dose and time dependent manner. In contrast, CRH-R2 levels in skeletal muscle increased following exposure to endotoxin. These results suggest that CRH-R2 may be differentially regulated in cardiac tissue and skeletal muscle. Finding that CRH-R2 expression in the heart is modulated by endotoxin, a potent inducer of cardiovascular dysregulation, suggests a possible link between CRH and the cardiovascular response to stress.
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PMID:Endotoxin regulates corticotropin-releasing hormone receptor 2 in heart and skeletal muscle. 929 75

Novel subtype of corticotropin-releasing hormone receptor (CRHR), designated type-2 CRHR (CRHR-2), mRNA was expressed not only in the central nervous system but also in the peripheral tissues such as the heart and skeletal muscle. The previous finding that type-1 CRHR mRNA is not detected in heart leads us to speculate that systemic administration of CRH induces hypotensive effects through CRHR-2, and that alterations in CRHR-2 in the heart may be implicated in blood pressure regulation. Therefore we examined CRHR-2 mRNA expression in the heart (at the level of ventricle) in spontaneously hypertensive rats (SHR) or DOCA-salt hypertensive rats (DOCA) using in situ hybridization histochemistry, compared to age-matched normotensive control rats. CRHR-2 mRNA levels in the heart were significantly higher in 7-week-old SHR than in 12-week-old SHR. Furthermore, CRHR-2 mRNA levels in SHR heart were significantly higher than those in normotensive controls, Wistar-Kyoto rats (WKY), at both 7 and 12 weeks of age. In contrast, CRHR-2 mRNA levels in DOCA heart were significantly lower than that of sham-operated controls after 6-weeks of treatment. Thus, alterations of CRHR-2 mRNA are dependent on the strain or experimental condition rather than as a consequence of hypertension. Plasma CRH levels in SHR or DOCA were not different from their normotensive control rats. CRH content in the ventricular heart of SHR or DOCA were also similar to normotensive controls. These results suggest that heart CRHR-2 mRNA levels are not influenced by circulating or locally existing CRH. Since alterations in heart CRHR-2 mRNA, as seen in SHR and DOCA, were bi-directional, the role of heart CRHR-2 in the regulation of hypertension remains to be elucidated.
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PMID:Type 2 corticotropin-releasing hormone receptor mRNA expression in the heart in hypertensive rats. 946 63

Whole-cell patch-clamp and extracellular field recordings were obtained from 450-microns-thick brain slices of infant rats (10-13 days postnatal) to determine the actions of corticotropin-releasing hormone on glutamate- and GABA-mediated synaptic transmission in the hippocampus. Synthetic corticotropin-releasing hormone (0.15 microM) reversibly increased the excitability of hippocampal pyramidal cells, as determined by the increase in the amplitude of the CA1 population spikes evoked by stimulation of the Schaffer collateral pathway. This increase in population spike amplitude could be prevented by the corticotropin-releasing hormone receptor antagonist alpha-helical (9-41)-corticotropin-releasing hormone (10 microM). Whole-cell patch-clamp recordings revealed that, in the presence of blockers of fast excitatory and inhibitory synaptic transmission, corticotropin-releasing hormone caused only a small (1-2 mV) depolarization of the resting membrane potential in CA3 pyramidal cells, and it did not significantly alter the input resistance. However, corticotropin-releasing hormone, in addition to decreasing the slow afterhyperpolarization, caused an increase in the number of action potentials per burst evoked by depolarizing current pulses. Corticotropin-releasing hormone did not significantly change the frequency, amplitude or kinetics of miniature excitatory postsynaptic currents. However, it increased the frequency of the spontaneous excitatory postsynaptic currents in CA3 pyramidal cells, without altering their amplitude and single exponential rise and decay time constants. Corticotropin-releasing hormone did not change the amplitude of the pharmacologically isolated (i.e. recorded in the presence of GABAA receptor antagonist bicuculline) excitatory postsynaptic currents in CA3 and CA1 pyramidal cells evoked by stimulation of the mossy fibers and the Schaffer collaterals, respectively. Current-clamp recordings in bicuculline-containing medium showed that, in the presence of corticotropin-releasing hormone, mossy fiber stimulation leads to large, synchronized, polysynaptically-evoked bursts of action potentials in CA3 pyramidal cells. In addition, the peptide caused a small, reversible decrease in the amplitude of the pharmacologically isolated (i.e. recorded in the presence of glutamate receptor antagonists) evoked inhibitory postsynaptic currents in CA3 pyramidal cells, but it did not significantly alter the frequency, amplitude, rise and decay time constants of spontaneous or miniature inhibitory postsynaptic currents. These data demonstrate that corticotropin-releasing hormone, an endogenous neuropeptide whose intracerebroventricular infusion results in seizure activity in immature rats, has diverse effects in the hippocampus which may contribute to epileptogenesis. It is proposed that the net effect of corticotropin-releasing hormone is a preferential amplification of those incoming excitatory signals which are strong enough to reach firing threshold in at least a subpopulation of CA3 cells. These findings suggest that the actions of corticotropin-releasing hormone on neuronal excitability in the immature hippocampus may play a role in human developmental epilepsies.
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PMID:The pro-convulsant actions of corticotropin-releasing hormone in the hippocampus of infant rats. 952 63

Among the more consistent observations in patients with major depression is dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis presenting as elevation of basal cortisol, dexamethasone-mediated negative feedback resistance, increased cerebrospinal fluid levels of corticotropin-releasing factor (CRF), and a blunted adrenocorticotropic hormone (ACTH) response to challenge with exogenous CRF. These features appear to be state, rather than trait markers, and are normalized upon successful treatment. These pathophysiologic adaptations may arise from defects in central drive to the neuroendocrine hypothalamus, disruption of normal adrenocortical hormone receptor function or a modification of HPA axis function at any level. Functional assessment of the HPA axis is thought to provide a window into central nervous system operation that may be of diagnostic value in this and other affective disorders regardless of whether CRF and glucocorticoids are directly involved in the origin of major depression or merely exacerbate the consequences of other primary defects.
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PMID:Psychoneuroendocrinology of depression. Hypothalamic-pituitary-adrenal axis. 967 Feb 27

Both urocortin (UCN) and corticotropin-releasing hormone (CRH) are known to stimulate secretion of adrenocorticotropic hormone (ACTH) by corticotroph cells via type-1 corticotropin-releasing hormone receptor (CRHR-1). We extensively examined UCN effects on the anterior pituitary (AP), particularly on proopiomelanocortin (POMC) mRNA and CRHR-1 mRNA as well as ACTH secretion in vivo. Moreover, signal transduction with UCN exposure was assessed in AP cell cultures in comparison with transduction following CRH exposure. Intravenously administered of UCN (5 microg/kg) increased ACTH and corticosterone secretion. Similarly, intravenous administration of UCN increased POMC mRNA and decreased CRHR-1 mRNA in the AP. These UCN effects were more potent and long-lasting than those of CRH. The prominent effect of UCN on ACTH secretion in vivo was confirmed in AP cell cultures, where application of UCN stimulated ACTH release approximately 7 times more strongly than CRH. The effect of UCN on ACTH release was enhanced by phorbol esters which activate protein kinase C, but was reduced by the selective cAMP-dependent protein kinase inhibitor, H-89. These results suggest that, as with CRH, UCN stimulates ACTH production and/or release through cAMP-dependent mechanisms, and that protein kinase C-dependent mechanism has a synergistic effect upon UCN-induced ACTH release. The more potent effects of UCN relative to CRH may be attributable to UCN's higher affinity for CRHR-1.
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PMID:Effect of urocortin on ACTH secretion from rat anterior pituitary in vitro and in vivo: comparison with corticotropin-releasing hormone. 973 15

In the rat, high-dose corticosterone (Cort) administration, the hypercortisolism of starvation, and adrenalectomy are all associated with decreased food intake and weight loss. We report here a study of the effects of high-dose Cort administration, starvation, and adrenalectomy on two peripheral hormones known to influence food intake and energy use, insulin and leptin. We also studied the impact of these interventions on the levels of type 2 corticotropin-releasing hormone receptor (CRHR-2) mRNA in the hypothalamic paraventricular nucleus (PVN) and ventromedial hypothalamus (VMH). The VMH is classically referred to as the satiety center because electrical stimulation of the VMH leads to inhibition of food intake, whereas CRHR-2 are thought to transduce the profound anorexogenic effects of CRH or its related peptide urocortin. Starvation and adrenalectomy each lowered plasma insulin and leptin levels and were associated with decrements in CRHR-2 mRNA levels in the VMH. Cort administration increased plasma leptin levels profoundly, as well as plasma insulin levels and the levels of VMH CRHR-2 mRNA. Under all experimental conditions, a positive correlation was seen between plasma leptin levels and VMH CRHR-2 mRNA. These data suggest that decreased food intake and weight loss after high-dose Cort administration at least partially depend on the profound impact of Cort on plasma leptin secretion in the rat; they suggest, moreover, an additional mechanism for the satiety-inducing effects of leptin, namely increasing CRHR-2 in the VMH. The concordance of a fall in plasma insulin and leptin levels with the fall in VMH CRHR-2 mRNA levels further supports the idea that compensatory responses during starvation and adrenalectomy include not only the disinhibiting effects of reduced insulin and leptin levels on appetite through already-described mechanisms but also via an effect of leptin on VMH CRHR-2. Neither Cort administration, starvation, nor adrenalectomy influenced the levels of CRHR-2 mRNA in the PVN, suggesting that these receptors are differentially regulated in different hypothalamic regions.
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PMID:Altered expression of type 2 CRH receptor mRNA in the VMH by glucocorticoids and starvation. 975 44

The hippocampus plays an important role in central stress integration. The present study tests the hypothesis that the ventral subiculum, as a principal source of hippocampal efferents, is involved in co-ordination of hypothalamo-pituitary-adrenocortical and behavioural responses to cognitively-processed information. Basal hypothalamo-pituitary-adrenocortical activation appears to be normal in ventral subiculum lesion rats, as basal corticosterone and adrenocorticotropic hormone secretion, anterior pituitary pro-opiomelanocortin and type 1 corticotropin-releasing hormone receptor messenger RNA expression, adrenal and thymus weight, and splenic mitogen activity are not affected by lesion. Lesions of the ventral subiculum induce glucocorticoid hypersecretion following restraint stress or open field exposure, whereas responses to ether inhalation are unaffected. Interestingly, ventral subiculum lesion does not affect fast glucocorticoid negative feedback inhibition of restraint-induced adrenocorticotropic hormone release. Corticotropin-releasing hormone immunoreactivity is increased in the hypothalamic paraventricular nucleus of ventral subiculum lesion rats, and is differentially depleted by acute stress exposure (relative to sham-lesion rats). However, ventral subiculum lesion does not affect basal and stress-induced corticotropin-releasing hormone, arginine vasopressin and cFOS messenger RNA expression in paraventricular nucleus neurons. Behavioural analysis reveals that ventral subiculum lesion rats are hyper-responsive to open field exposure, showing decreased total ambulation and reduced incidence of central square entry. The results suggest that the ventral subiculum plays a specific role in integrating cognitively-processed stimuli (e.g., restraint and open field exposure) into appropriate neuroendocrine and behavioural responses to stress. Enhanced stress-induced glucocorticoid secretion and increased corticotropin-releasing hormone biosynthesis are likely due to removal of oligosynaptic inhibitory input to the paraventricular nucleus subsequent to ventral subiculum lesion.
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PMID:Ventral subiculum regulates hypothalamo-pituitary-adrenocortical and behavioural responses to cognitive stressors. 988 60

The hypothalamic neuropeptide corticotropin-releasing hormone is the major hypothalamic regulator of the endocrine pituitary-adrenal axis. Corticotropin-releasing hormone is also expressed in many peripheral sites, where its functions are unclear. It is also secreted by diverse neoplasms, where it may be associated with malignant behavior. To provide information regarding the function of corticotropin-releasing hormone in peripheral sites and in tumors, we asked whether corticotropin-releasing hormone has angiogenic properties. In vitro, we found that human corticotropin-releasing hormone specifically stimulates endothelial chemotaxis via a corticotropin-releasing hormone receptor-dependent mechanism. In vivo, subcutaneous inoculation of nude mice with human epithelial tumor cells engineered to secrete corticotropin-releasing hormone was associated with significantly enhanced angiogenesis (2.3-fold over control) and tumor growth (5-fold over control). Peripheral corticotropin-releasing hormone may thus enhance local angiogenesis, which may provide clues to its function outside of the nervous system.
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PMID:Corticotropin-releasing hormone stimulates angiogenesis and epithelial tumor growth in the skin. 1057 42


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