Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0043167 (pertussis)
19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Melatonin has been found to inhibit or enhance the constitutive secretion of proteins from the cultured melanoma cells at nanomolar concentrations (0.5-10 nM), in a dose dependent manner. The amplitude and direction of the response were found to depend on cell density: melatonin inhibited the release early after plating or at low cell density, but facilitated the release later on, or at high cell density. To elucidate the involvement of G-proteins in these responses, the effects of guanosine 5'-O-(3-thiotriphosphate) (GTP tau S; which was introduced into the cells during the process of permeabilization and resealing with ATP), aluminum fluoride, pertussis and cholera toxins on protein secretion from the cells were assessed in the absence and presence of melatonin. At low cell density, melatonin inhibited release, but paradoxically enhanced it when GTP hydrolysis was blocked (by GTP tau S or cholera toxin treatment). Aluminum fluoride and melatonin inhibited protein release in the absence or presence of GTP tau S. At high cell density, melatonin facilitated the release and so did GTP tau S, aluminum fluoride, their combination, and cholera toxin treatment. However, in the presence of the combination of GTP tau S, aluminium fluoride and melatonin, protein release was paradoxically inhibited. Similar treatment of the cells with pertussis toxin, did not affect the melatonin-mediated inhibition or facilitation. These results indicate that the effects of melatonin on protein secretion are mediated by at least one heterotrimeric G protein which belongs to the Gs class. In addition, melatonin can facilitate secretion via a cholera and pertussis toxins-insensitive mechanism which can be inhibited by aluminum fluoride. This effect is manifested when Gs is permanently activated (by GTP tau S or cholera toxin).
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PMID:Facilitation and inhibition of G-protein regulated protein secretion by melatonin. 758 Aug 73

In neonatal rat pituitary, melatonin inhibits GnRH-induced increase of cAMP and [Ca2+]i. Both effects are transduced by specific high-affinity melatonin receptors coupled with pertussis toxin-sensitive G-protein. We have attempted to determine whether melatonin acts via independent pathways on both messengers or whether the indole directly inhibits only one of the messengers and the second is decreased as a secondary consequence. Melatonin inhibition of cAMP accumulation was not prevented by agents known to block melatonin effect on [Ca2+]i such as Na(+)- or Ca2(+)-free medium, Bay K, nifedipine, KCl or gramicidin. Melatonin effect on [Ca2+]i was not prevented by forskolin or 8-bromo-cAMP. We therefore conclude that melatonin inhibits cAMP accumulation and [Ca2+]i increase independently by separate pathways.
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PMID:Melatonin inhibits increase of intracellular calcium and cyclic AMP in neonatal rat pituitary via independent pathways. 776 26

Melatonin and 5-methoxytryptamine inhibited forskolin-stimulated cyclic AMP formation in cultured neural cells prepared from embryonic chick retina. Both methoxyindoles exhibited similar potency and efficacy, with EC50 values of 0.8 nM for melatonin and 7.2 nM for 5-methoxytryptamine. Inhibition of cyclic AMP formation by 5-methoxytryptamine or melatonin was prevented by pretreatment with pertussis toxin. Pretreatment of cultures with 5-methoxytryptamine for 24 h reduced the subsequent inhibitory cyclic AMP response to 5-methoxytryptamine but not that to 2-iodomelatonin. Putative melatonin receptors on cultured retinal cells were labeled with 2-[125I]iodomelatonin. Melatonin displaced specific 2-[125I]iodomelatonin with a Ki value (0.8 nM) similar to the EC50 for inhibition of cyclic AMP formation. In contrast, 5-methoxytryptamine only inhibited 2-[125I]iodomelatonin binding at very high concentrations (Ki = 650 nM). Pretreating cultured cells for 24 h with 2-iodomelatonin or melatonin, but not with 5-methoxytryptamine, reduced subsequent 2-[125I]iodomelatonin binding. Thus, 5-methoxytryptamine appears to inhibit forskolin-stimulated cyclic AMP formation at a site distinct from the 2-iodomelatonin binding site.
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PMID:5-Methoxytryptamine inhibits cyclic AMP accumulation in cultured retinal neurons through activation of a pertussis toxin-sensitive site distinct from the 2-[125I]iodomelatonin binding site. 789 Nov 20

The aims of this study were to characterize the melatonin receptors in rat brain arteries forming the circle of Willis. Saturation studies performed using in vitro autoradiography and [125I]iodomelatonin revealed the presence of two binding sites: one with a Kd of 13 pM, and the second characterized by a Kd of 832 pM. Coincubation with a nonhydrolyzable guanine nucleotide analog [guanosine-5'-O-(3-thiotriphosphate)] inhibited 2-[125I]iodomelatonin binding in a concentration-dependent manner, whereas adenine nucleotide adenosine-5'-O-(3-thiotriphosphate) was ineffective. In saturation studies performed in the presence of guanosine-5'-O-(3-thiotriphosphate), the high affinity site was no longer detectable, and the affinity of the receptor was decreased to the high picomolar range. Melatonin, at nanomolar concentrations, was able to inhibit forskolin-stimulated cAMP production in rat circle of Willis arteries. Preincubation with pertussis toxin counteracted the effect of melatonin. Our results demonstrate that melatonin receptors in rat cerebral arteries are linked to their second messenger through a pertussis toxin-sensitive G-protein, similar to what has been described for melatonin receptors in different areas of vertebrate brain.
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PMID:Characterization of melatonin receptors and signal transduction system in rat arteries forming the circle of Willis. 801 71

Melatonin (MEL) plays a central role in the regulation of seasonal cycles and in the control of circadian rhythms in mammals. Functional MEL-sensitive receptors were expressed in Xenopus laevis oocytes following injection of poly (A)+ RNA from rat brain. Administration of 0.1-100 micromol/l MEL to voltage-clamped oocytes (holding potential: -70 mV) elicited oscillatory inward currents (reversal potential: -24 mV) which could be blocked by 9-anthracenecarboxylic acid and caffeine. After preincubation with pertussis toxin (PTX) the MEL response disappeared. The expressed MEL-sensitive receptor probably activates Ca(2+)-dependent chloride currents via a PTX-sensitive G protein and the phosphoinositol pathway.
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PMID:Expression and functional characterization of a melatonin-sensitive receptor in Xenopus oocytes. 864 48

The human ML1A melatonin receptor is expressed in the suprachiasmatic nucleus of the hypothalamus and is believed to regulate circadian rhythms. We report the kinetic characteristics and pharmacological profile of 2-[125I]iodomelatonin binding and the signaling pathway and agonist regulation of the human ML1A melatonin receptor stably expressed in Chinese hamster ovary cells. Association of 2-[125I]iodomelatonin binding was maximal by 1.5 hr at 37 degrees and fully dissociated on the addition of 1 microM melatonin. The binding of 2-[125I]iodomelatonin was saturable and of high affinity (KD = 74 +/- 14 PM, Bmax = 679 +/- 88 fmol/mg protein; three experiments). The pharmacological profile of various melatonin analogues revealed a profile (2-iodomelatonin > or = melatonin > N-acetyl serotonin > luzindole) characteristic of an ML1 subtype. Competition of melatonin for 2-[125I]iodomelatonin binding to the human ML1A receptor in lysed or intact cells resulted in biphasic curves revealing the existence of super high (approximately 20%) and high (approximately 80%) affinity states of the receptor. Guanosine-5'-0-(3-thio)triphosphate (100 PM-30 microM) when added alone inhibited 2-[125I]iodomelatonin binding (IC50 = 0.87 +/- 0.12 microM; three experiments), suggesting uncoupling of the receptor from G proteins. In addition, guanosine-5'-O-(3-thio)triphosphate (3 microM) produced a right-ward shift in both the super high and high binding melatonin affinities for 2-[125I]iodomelatonin resulting in monophasic curves. Melatonin (0.1 fM-1 nM) inhibited forskolin-induced cAMP formation in a concentration-dependent and biphasic manner. Low concentrations of melatonin (0.01 fM-1 PM) inhibited forskolin (100 microM)-stimulated cAMP formation with an IC50 of 0.1 +/- 0.05 PM (four experiments) and a maximal inhibitory effect (26%) at 1 PM. Higher concentrations of melatonin (1 PM-1 nM) inhibited forskolin-induced cAMP formation with an IC50 of 64 +/- 1.8 PM (four experiments) and a maximal inhibition (74%) at 1 nM. Luzindole (1 microM), a competitive melatonin receptor antagonist, antagonized the effect of melatonin at the higher concentrations only (IC50 = 1.5 +/- 0.22 nM, pKB = -7.3; three experiments). Pretreatment with pertussis toxin completely abolished melatonin-mediated inhibition of forskolin-induced cAMP formation through these receptors. Pretreatment with various concentrations of melatonin (0.1 PM-1 microM) for different periods of time (1, 6, 18, and 24 hr) did not decrease 2-[125I]iodomelatonin binding. However, competition by melatonin for 2-[125I]iodomelatonin binding to cells pretreated with melatonin and washed was only to a single population of super high affinity sites (IC50 = 1.1 +/- 0.28 nM; three experiments) as revealed by monophasic curves. Cells pretreated with melatonin revealed a persistent inhibition (approximately 20%) of forskolin-induced cAMP formation that was not reversed by extensive washes (up to 1 hr) or when luzindole (1 microM) was added together with melatonin during pretreatment. These results suggest that tight binding of melatonin to the super high affinity state of the human ML1A melatonin receptor may be the mechanism by which low concentrations of circulating hormone in vivo regulates signaling in the suprachiasmatic nucleus of the hypothalamus.
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PMID:Characterization and regulation of the human ML1A melatonin receptor stably expressed in Chinese hamster ovary cells. 870 Jan 9

The effect of pinealectomy on the characteristics of melatonin receptors in the chicken kidney was studied. One-day-old chicks were operated and kept under a 12 h/12 h light/dark photoperiod. Six weeks after operation, the animals were sacrificed at mid-light and mid-dark. Serum melatonin was determined by radioimmunoassay and kidney melatonin receptors were studied by radioreceptor assay using the melatonin agonist 2-[125I]iodomelatonin as the radioligand. Pinealectomy significantly reduced the mid-dark serum melatonin level and abolished the diurnal rhythm of 2-[125I]-iodomelatonin binding in the kidney. The density of 2-[125I]-Iodomelatonin binding sites in the kidney at mid-dark was increased significantly to a value comparable to the mid-light density after pineal ablation. Our results suggest that melatonin receptors in the chicken kidney are directly regulated by melatonin in the circulation. The coupling of kidney melatonin receptors to adenylate cyclase was investigated. The basal and forskolin-stimulated cAMP production in chicken kidney explants was studied following melatonin or melatonin plus pertussis toxin treatment. Levels of cAMP in chicken kidney explants were extracted and determined by radioimmunoassay. Melatonin had no effect on basal cAMP levels. However, melatonin significantly inhibited the forskolin-stimulated cAMP accumulation at a concentration of 10 pmol/l. Inhibitory effects of melatonin on the forskolin-stimulated cAMP increase in the chicken kidney were totally blocked by preincubating the kidney tissue with 1.0 micrograms/ml pertussis toxin. Our results suggest that kidney melatonin receptors may modulate the adenylate cyclase leading to biological responses in the renal system.
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PMID:Melatonin receptors in the chicken kidney are up-regulated by pinealectomy and linked to adenylate cyclase. 876 84

G-proteins define both the pharmacological characteristics and the signalling pathways of G-protein-coupled receptors. Melatonin receptors have been shown to belong to this class of receptors through their sensitivity to modulators of G-protein function. This study reveals that 2-125I-iodomelatonin (125I-MEL) binding to different target tissues is differentially affected by agents which disrupt the G-protein cycle. GTP gamma S, pertussis (PTX) and cholera (CTX) toxins each reduce 125I-MEL binding to ovine pars tuberalis (oPT) and lizard brain membranes, whereas chicken brain is affected only by GTP gamma S (guanosine 5'-O-(3-thiotriphosphate)) and CTX. In contrast, high affinity binding of 125I-MEL in the ovine hippocampus was not affected by any of these agents. This finding, together with the fact that neural binding sites of the sheep brain were found to have markedly lower molecular mass than those of the oPT on native gel electrophoresis (365 vs 525 kDa), suggests that the neural 125I-MEL binding sites in sheep may not be G-protein coupled. Pharmacologically, however, the binding sites in the hippocampus and oPT could not be distinguished using 11 analogues of melatonin. Therefore, these data support the notion not only of multiple forms of melatonin receptor/G-protein complex, but of high affinity binding sites for 125I-MEL which do not display sensitivity to guanine nucleotides.
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PMID:Differential regulation of melatonin receptors in sheep, chicken and lizard brains by cholera and pertussis toxins and guanine nucleotides. 881 43

The recent cloning of a family of high affinity melatonin receptors has provided us with a unique opportunity to define the signal transduction pathways used by these receptors. We have studied signaling through the human Mel1a receptor subtype by stable expression of receptor complementary DNA in NIH 3T3 cells. Our data indicate that the human Mel1a receptor is coupled to inhibition of forskolin-stimulated cAMP accumulation by a pertussis toxin-sensitive G protein. Although melatonin alone is without effect on phosphoinositide hydrolysis, it potentiates the effects of PGF2 alpha stimulation on phospholipase C activation. Melatonin potentiates arachidonate release stimulated by PGF2 alpha and by ionomycin. The effects of melatonin on arachidonate release are sensitive to inhibition of protein kinase C. They are independent of the effects of melatonin on cAMP and do not appear to involve activation of mitogen-activated protein kinase. The effects of melatonin on both phosphoinositide hydrolysis and arachidonate release are sensitive to pertussis toxin treatment. Thus, we show that the melatonin signal is transduced by parallel pathways involving inhibition of adenylyl cyclase and potentiation of phospholipase activation.
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PMID:The Mel1a melatonin receptor is coupled to parallel signal transduction pathways. 897 29

Melatonin, the principal hormone of the vertebrate pineal gland, has been implicated in a variety of neurobiological processes such as circadian rhythmicity and reproductive function. One of the earliest described actions of melatonin was its ability to cause pigment translocation in the dermal melanophores of amphibians. Melatonin binding sites have been identified in the brain of many species and in pigmented tumour cell lines; however, the dermal melanophores of the frog Xenopus Laevis possess the highest known density of melatonin binding sites. These cells are the source from which a melatonin receptor has been cloned and provide an excellent model to study melatonin-mediated signal transduction in an isolated cell system. In Xenopus melanophores, melatonin induces a rapid perinuclear aggregation of intracellular pigment which is associated with a pertussis toxin-sensitive inhibition of cAMP. We have previously demonstrated that a subtype of melatonin binding sites found in selected regions of the pigeon brain and in Syrian Hamster RPMI 1846 melatonin cells are functionally coupled to phosphoinositide hydrolysis as a second messenger. Here we now present evidence to suggest that Xenopus Laevis melanophores also possess melatonin binding sites which are functionally linked to phosphoinositide hydrolysis. Melatonin agonists induced phosphoinositide hydrolysis in melanophores in a concentration-dependent manner with a rank order of potency of 2-iodomelatonin > 6-chloromelatonin > N-acetylserotonin > melatonin. Stimulatory response of 2-iodomelatonin was blocked by the melatonin antagonist N-acetyltryptamine and the alpha-adrenergic antagonist prazosin, which has been shown to have high affinity for melatonin binding sites. Phosphoinositide hydrolysis induced by melatonin agonists was not blocked by the serotonin antagonist ketanserin or by phentolamine, an alpha-adrenergic antagonist, indicating that the response observed was not due to stimulation of 5-HT2a/2c receptors or alpha-adrenergic receptors. Furthermore, incubation of melanophores with the non-hydrolyzable G-protein source GTP-gamma-S attenuated the phosphoinositide dose response induced by 2-iodomelatonin, and pre-incubation of the cells with pertussis toxin had no effect on 2-iodomelatonin-induced phosphoinositide hydrolysis. The present data suggest that Xenopus Laevis Melanophores possess G-protein linked pertussis toxin-insensitive melatonin binding sites which are functionally coupled to phosphoinositide hydrolysis as a signal transduction mechanism.
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PMID:Melatonin agonists induce phosphoinositide hydrolysis in Xenopus laevis melanophores. 911 16


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