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)

The melanotropic actions of alpha-melanocyte-stimulating hormone (alpha-MSH) and other melanocortins are mediated by activation of the melanocortin 1 receptor (MC1R). This G protein-coupled receptor is positively coupled to Gs and triggers the cyclic adenosine mono-phosphate (cAMP) pathway. Mutations of the MC1R gene are associated with skin type and pigmentation phenotypes, and with increased risk of skin cancers. Genetic studies have demonstrated an heterozygote carrier effect for these associations, suggesting the importance of variant allele dosage. This could be accounted for, at least partially, if the number of MC1R molecules, rather than the Gs protein or the effector enzyme, adenylyl cyclase, is limiting for the activation of the signalling pathway. However, the nature of the limiting factor(s) in MC1R signalling has not been investigated. We addressed this question by comparing the cAMP output of clones of human melanoma cell lines enriched in MC1R by stable transfection. We also analysed heterologous cell systems widely used for functional studies of MC1R. We show that cAMP production in clones of Chinese hamster ovary cells stably expressing the MC1R is a linear function of receptor number up to high, supraphysiological levels of approximately 50,000 alpha-MSH binding sites per cell. Enrichment of human melanoma cell lines with MC1R also results in increased cAMP levels, with a small leftward shift of the agonist dose-response curves. Therefore, at physiological expression levels second-messenger generation is dependent on receptor density. Within melanoma cells and also likely in normal melanocytes, MC1R appears the limiting factor controlling the output of the cAMP signalling pathway.
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PMID:Rate limiting factors in melanocortin 1 receptor signalling through the cAMP pathway. 1295 Jul 34

Self-renewal and differentiation of embryonic stem (ES) cells are controlled by the combinatorial action of extracellular signals and regulation of gene expression. For characterizing the entire molecular mechanism governing these events, we first established a feeder- and serum-free culture system in which mouse ES cells could propagate in clonal density in keeping with proper pluripotency. Supplementation of peptide hormones such as adrenocorticotropic hormone (ACTH) is required to remove serum, and the key event in this phenomenon may be the inhibition of the adenylyl cyclase (AC) activity, as it replaces the effect of these peptides. Because ES cells themselves produce the same activity, the finding suggests a novel mechanism in which activation of AC restricts clonal propagation of pluripotent stem cells.
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PMID:A novel mechanism for regulating clonal propagation of mouse ES cells. 1514 75

The aim of the present study was to investigate the direct effects and action mechanisms of digitalis on the production of corticosterone in rat adrenocortical cells. Male rats were challenged with digoxin (1 microg ml(-1) kg(-1)) in the presence or absence of adrenocorticotropin (ACTH, 5 microg ml(-1) kg(-1)) administered by intravenous injection to the right jugular vein. Blood samples were collected at 0, 30, 60, and 120 min following the challenge. The concentration of corticosterone in the rat plasma samples was measured by radioimmunoassay. Zona fasciculata-reticularis (ZFR) cells in male rats were prepared and then incubated with or without digoxin or digitoxin in the presence or absence of ACTH (10(-9) m), forskolin (10(-7) m), 8-bromo-cyclic 3' : 5'-adenosine monophosphate (10(-4) m), cyclopiazonic acid (CPA, 10(-5) m), trilostane (10(-6) m), 25-OH-cholesterol (10(-5) m), pregnenolone (10(-5) m), progesterone (10(-5) m), or deoxycorticosterone (10(-5) m) at 37 degrees C for 1 h before collection of the media. Corticosterone or pregnenolone levels were measured by radioimmunoassay. A single injection of digoxin did not alter the basal level of plasma corticosterone, but did inhibit the level of plasma corticosterone released in response to ACTH in vivo. Administration of digoxin or digitoxin decreased both spontaneous and ACTH-stimulated release of corticosterone in vitro. Digoxin (10(-7)-10(-5) m) and digitoxin (10(-7)-10(-5) m), but not ouabain (10(-7)-10(-5) m), dose-dependently inhibited corticosterone production in response to forskolin and 8-Br-cyclic AMP in rat ZFR cells. Both digoxin (10(-6)-10(-5) m) and digitoxin (10(-6)-10(-5) m) attenuated corticosterone production in response to CPA. Digoxin (10(-5) m) or digitoxin (10(-5) m) inhibited cytochrome P450 side-chain cleavage enzyme (cytochrome P450scc) activity (catalyses conversion of cholesterol to pregnenolone in the presence of trilostane) in rat ZFR cells. The enzyme activity of 11 beta-hydroxylase (catalyses conversion of deoxycorticosterone to corticosterone) in ZFR cells was also inhibited by the administration of digoxin (10(-5) m) or digitoxin (10(-5) m).10 These results together suggest that digoxin and digitoxin decrease the release of corticosterone by acting directly on ZFR cells via a Na+, K+-ATPase-independent mechanism involving the inhibition of the activities of adenylyl cyclase, cytochrome P450scc and 11 beta-hydroxylase, as well as the functioning of cyclic AMP and intracellular calcium.
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PMID:Inhibitory effects of digoxin and digitoxin on corticosterone production in rat zona fasciculata-reticularis cells. 1524 23

The melanocortins (alpha-melanocyte-stimulating hormone and adrenocorticotropin) act on epidermal melanocytes to increase melanogenesis, the eumelanin/pheomelanin ratio and dendricity. These actions are mediated by the heptahelical melanocortin 1 receptor (MC1R), positively coupled to adenylyl cyclase. Gain-of-function mouse Mc1r alleles are associated with a dark, eumelanic coat. Conversely, loss-of-function variants, or overexpression of agouti, a natural melanocortin antagonist, yield yellow, pheomelanic furs. In humans, loss-of-function MC1R variants are associated with fair skin, poor tanning, propensity to freckle and increased skin cancer risk. Therefore, MC1R is a key regulator of mammalian pigmentation. Several observations such as induction of constitutive pigmentation in amelanotic mouse melanoma cells following expression of MC1R indicate that the receptor might display agonist-independent activity. We report a systematic and comparative study of MC1R and Mc1r constitutive activity. We show that expression of MC1R in heterologous systems leads to an agonist-independent increase in cyclic adenosine monophophate (cAMP). Basal signalling is a function of receptor expression and is two to fourfold higher for MC1R than for Mc1r. Moreover, it is observed in human melanoma cells over-expressing the MC1R. Constitutive signalling is abolished or reduced by point mutations of MC1R impairing the response to agonists, and is only doubled by the Lys94Glu mutation, mimicking the constitutively active mouse E(so-3J) allele. Stable or transient expression of wild-type MC1R, but not of loss-of-function mutants, potently stimulates forskolin activation of adenylyl cyclase, a common feature of constitutively active Gs-coupled receptors. Therefore, human MC1R displays a strong agonist-independent constitutive activity.
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PMID:Agonist-independent, high constitutive activity of the human melanocortin 1 receptor. 1525 Sep 41

1 Naloxone benzoylhydrazone (NalBzoH) has initially been developed as an agonist of the pharmacologically defined kappa3-opioid receptor and has recently been employed as an antagonist at the opioid receptor-like (ORL1) receptor. In the present study, we investigated the ability of NalBzoH to elicit agonist-like effects on receptor signalling in distinct layers of rat olfactory bulb, a brain region where we have demonstrated the presence of opioid and ORL1 receptors coupled to both stimulation and inhibition of cyclic AMP formation. 2 In membranes of the olfactory nerve-glomerular layer (ON-GL), external plexiform layer (EPL) and granule cell layer (GRL), NalBzoH elicited a concentration-dependent stimulation of guanosine-5'-O-(3-[35S]-thio)triphosphate ([35S]GTPgammaS) binding with pEC50 values ranging from 7.36 to 7.86, whereas the kappa1-opioid receptor agonists (-)-U-50,488 and U-69,593 were inactive. 3 In membranes of GRL, but not ON-GL and EPL, NalBzoH stimulated basal adenylyl cyclase activity by 40% with a pEC50 of 8.14, and significantly potentiated the net enzyme stimulation elicited by corticotropin-releasing hormone and pituitary adenylate cyclase-activating peptide 38. Pertussis toxin prevented the NalBzoH stimulations of [35S]GTPgammaS binding and adenylyl cyclase activity. 4 In membranes of EPL and GRL, but not ON-GL, NalBzoH elicited a concentration-dependent inhibition of forskolin-stimulated adenylyl cyclase activity with pEC50 values of 8.07 and 8.08, respectively. 5 At concentrations that completely blocked the actions of nociceptin/orphanin FQ (N/OFQ), the ORL1 receptor antagonists CompB and [Nphe1]N/OFQ(1-13)NH2 failed to antagonize either the stimulatory or the inhibitory effect of NalBzoH on cyclic AMP formation. Similarly, the kappa1-opioid receptor antagonist nor-binaltorphimine counteracted the NalBzoH effects with relatively low potencies (pKi values=7.67-8.09). 6 Conversely, the selective delta-opioid receptor antagonist TIPP (pKi=9.10) and the selective mu-opioid receptor antagonist CTAP (pKi=8.27) reduced the inhibitory effect of NalBzoH by 70 and 30%, respectively. Moreover, TIPP and CTAP potently inhibited the NalBzoH stimulation of cyclic AMP, each antagonist maximally causing 50% blockade of the agonist response. 7These data demonstrate that in the olfactory bulb NalBzoH activates receptor signalling by acting through delta- and mu-opioid receptors and independently of ORL1 and kappa1-opioid receptors.
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PMID:G protein activation and cyclic AMP modulation by naloxone benzoylhydrazone in distinct layers of rat olfactory bulb. 1545 72

The review presents our results on the regulatory role of prostaglandins (PG) and nitric oxide (NO) in the activation of hypothalamic-pituitary-adrenal (HPA) axis by cholinergic, adrenergic and histaminergic systems and by neurohormones: corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) under basal conditions. The synthesis of endogenous PG or NO was inhibited by non-selective and selective cyclooxygenase (COX) antagonists and nitric oxide synthase (NOS) blockers given 15 min before the respective receptor agonist and HPA axis activity was assessed 1 h later by measuring plasma ACTH and serum corticosterone levels. The muscarinic agent - carbachol-induced HPA response was considerably supressed by piroxicam, a predominantly constitutive cyclooxygenase (COX-1) inhibitor and significantly diminished by indomethacin, a non-selective COX blocker, but was unaffected by compound NS-398, an inducible cyclooxygenase (COX-2) antagonist. A non-selective NOS antagonist L-NAME and neuronal NOS blocker L-NNA significantly intensified the carbachol-induced corticosterone secretion. The nicotine-induced increase in ACTH and corticosterone response was significantly supressed by piroxicam, and diminished by indomethacin, but was significantly augmented by L-NAME and L-NNA. The inhibition of PG synthesis by indomethacin totally abolished or reversed the increase of nicotine-induced hormone responses to both NOS blockers. The i.c.v. phenylephrine, an alpha(1)-adrenergic receptor agonist - evoked HPA response was significantly impaired by piroxicam and compound NS-398 and more potently reduced by L-NAME. The i.c.v. clonidine, an alpha(2)-adrenergic agonist - elicited HPA response was also considerably decreased by piroxicam, compound NS-398 and L-NAME. By contrast, the stimulatory effect of i.c.v. isoprenaline, a non-selective beta-adrenergic agonist, was not altered by either COX or NOS inhibitors. The i.c.v. histamine- and HTMT, a histamine H(1)-agonist-induced ACTH and corticosterone response were significantly diminished by piroxicam and indomethacin, respectively. Compound NS-398, did not markedly alter the HPA response to HTMT or amthamine, a histamine H(2) receptor agonist. Inhibition of endogenous NO synthesis by a neuronal NOS inhibitor 7-nitroindazole markedly enhanced the histamine-induced hormone secretion, abolished the HTMT-induced response and did not substantially alter the amthamine-evoked ACTH and corticosterone secretion. COX blockers did not significantly affect the CRH-induced HPA response and the inhibition of NO synthesis by L-NNA markedly intensified ACTH response. The vasopressin-stimulated increase in HPA response, was considerably reduced by the inhibition of PG synthesis by both COX antagonists while inhibition of NO synthesis by NOS blockers greatly enhanced this response. The involvement of PG and NO in the neurohormonal regulation of HPA activity depends mainly on greatly complex and tightly regulated mechanisms at the level of second messengers IP(3) and adenylyl cyclase systems.
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PMID:Nitric oxide and prostaglandin systems in the stimulation of hypothalamic-pituitary-adrenal axis by neurotransmitters and neurohormones. 1561 36

Neurotransmitters are stimulatory as well as inhibitory regulators of cell migration. Angiotensin is such an inhibitory regulator of the SDF-1-induced migration of cytotoxic T lymphocytes, as we have investigated by time-lapse videomicroscopy and computer-assisted cell tracking. For angiotensin II, the most effective form of angiotensin for the inhibition of migration, two G protein-coupled receptors are known, which both downregulate the activity of the adenylyl cyclase via activation of inhibitory G proteins. This downregulation of the enzymatic activity is a key signaling event for the inhibition of T lymphocyte and tumor cell migration, while stimulatory neurotransmitters--for example, norepinephrine--cause an activation of the adenylyl cyclase. Similar to angiotensin, the SDF-1-induced migration of cytotoxic T lymphocytes was inhibited by DAMGO, a specific agonist for the mu-opioid receptor, which is coupled to inhibitory G proteins, too. More interestingly, DAMGO downregulated the met-enkephalin-induced migration of MDA-MB-468 breast carcinoma cells. Met-enkephalin binds to the delta-opioid receptor and, with lower affinity, to the mu-opioid receptor. Since the delta-opioid receptor also activates inhibitory G proteins, the promigratory effect of met-enkephalin is caused by an intracellular signaling distinct from the engagement of each opioid receptor alone. In summary, the dual control of the adenylyl cyclase functions as an integrator of stimulatory and inhibitory signals for T lymphocyte and tumor cell migration, which are delivered by neurotransmitters and other signal substances that bind to G protein-coupled receptors.
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PMID:Inhibition of cell migration via G protein-coupled receptors to opioid peptides and angiotensin. 1565 Feb 57

Amphibian pituitary melanotropes are used to investigate principles of neuroendocrine translation of neural input into hormonal output. Here, the steps in this translation process are outlined for the melanotrope cell of Xenopus laevis, with attention to external stimuli, neurochemical messengers, receptor dynamics, second-messenger pathways, and control of the melanotrope secretory process. Emphasis is on the pathways that neurochemical messengers follow to reach the melanotrope. The inhibitory messengers, dopamine, gamma-aminobutyric acid, and neuropeptide Y, act on the cells by synaptic input from the suprachiasmatic nucleus, whereas the locus coeruleus and raphe nucleus synaptically stimulate the cells via noradrenaline and serotonin, respectively. Autoexcitatory actions are exerted by acetylcholine, brain-derived neurotrophic factor (BDNF), and the calcium-sensing receptor. At least six messengers released from the pituitary neural lobe stimulate melanotropes in a neurohormonal way: corticotropin-releasing hormone, thyrotropin-releasing hormone, BDNF, urocortin, mesotocin, and vasotocin. They all are produced by the magnocellular nucleus and coexist in various combinations in two types of neurohemal axon terminal. Most of the relevant receptors of the melanotropes have been elucidated. Apparently, the neural lobe has a dominant role in activating melanotrope secretory activity. The intracellular mechanisms translating the various inputs into cellular activities like biosynthesis and secretion constitute the adenylyl cyclase-cAMP pathway and Ca(2+) in the form of periodic changes of the intracellular Ca(2+) concentration, known as Ca(2+) oscillations. It is proposed that the pattern of these oscillations encodes specific regulatory information and that it is set by first messengers that control, for example, via G proteins and cAMP-related events, specific ion channel-mediated events in the membrane of the melanotrope cell.
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PMID:Neuronal, neurohormonal, and autocrine control of Xenopus melanotrope cell activity. 1589 Oct 22

The objective of our study was to investigate the effect of stimulation of the cAMP-dependent pathway on the expression of an orphan nuclear receptor, SF-1/Ad4BP in mouse adrenal tumour, Y-1 cells in culture. We evaluated the temporal pattern of the effects of corticotropin (ACTH) and the adenylyl cyclase activator forskolin on the level of SF-1 mRNA, and compared the time course of induction of SF-1 with that of CYP11A1. Forskolin, corticotropin and 8-Br-cAMP significantly elevated the level of the SF-1 transcript, after 1.5 h of incubation, with a concomitant increase of SF-1 protein level, observed after 6 h. The CYP11A1 transcript increased gradually over the incubation period, and reached the maximal level after 12 to 24 h. The steady-state level of the SF-1 transcript was unaffected by forskolin when the cells were incubated with actinomycin D, indicating that stimulation of the cAMP pathway results in enhanced transcription of the gene. The effect of forskolin was augmented by cycloheximide, suggesting that an inhibitory protein, whose synthesis was inhibited by cycloheximide, could be involved in negative regulation of SF-1 expression. It is concluded that SF-1 expression is positively regulated by the cAMP pathway at the transcriptional level, and can represent the primary event in cAMP-mediated induction of steroid hormone synthesis in Y-1 cells.
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PMID:Temporal pattern of the induction of SF-1 gene expression by the signal transduction pathway involving 3',5'-cyclic adenosine monophosphate. 1591 8

Catecholamines are major stimulants of adipose tissue metabolism. Norepinephrine and epinephrine act through three subtypes of beta-adrenoceptors (beta-AR) expressed in the adipocytes. The aim of this work was to study the mechanisms of lipid mobilization in beta1/beta2/beta3-AR triple-knockout (beta-less) mice. Glycerol and nonesterified fatty acids released from isolated adipocytes were measured as an index of lipolytic activity. There was no difference between the two genotypes for basal lipolysis and lipolytic response to corticotropin or to agents acting at the adenylyl cyclase and protein kinase A levels. The lipolytic response to norepinephrine and beta-AR agonists was blunted in beta-less mice. However, a residual low-affinity lipolytic effect was observed in the presence of catecholamines and beta3-AR agonists but not of beta1- or beta2-AR agonists. cAMP levels were increased by a beta-AR agonist in white and brown adipocytes of beta-less mice. The residual lipolytic effect was blocked by beta-AR antagonists. It was mediated neither by alpha1- or alpha2-AR nor dopaminergic, serotonergic, and histaminergic by receptors. Bioinformatic analyses do not provide evidence for a fourth beta-AR. We conclude that the residual lipolytic effect observed in beta-less mice can be attributed to an unknown Gs-protein-coupled receptor with low affinity for catecholamines.
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PMID:Norepinephrine induces lipolysis in beta1/beta2/beta3-adrenoceptor knockout mice. 1593 97

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