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Query: UNIPROT:P06889 (Mol)
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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.
Mol Cell Endocrinol 1995 Feb
PMID:Melatonin inhibits increase of intracellular calcium and cyclic AMP in neonatal rat pituitary via independent pathways. 776 26

Twenty-four edible plants were investigated for the presence of melatonin, heretofore considered to be a molecule found only in the animal kingdom. The amount of melatonin in different plants varied greatly with highest melatonin being present in plants of the rice family. Melatonin was identified by radioimmunoassay and verified by high performance liquid chromatography with fluorescence detection. Feeding a diet containing plant products rich in melatonin to chicks increased radioimmunoassayable levels of melatonin in their blood. Likewise, melatonin extracted from plants inhibited binding of [125I]iodomelatonin to rabbit brain. Thus, melatonin ingested in foodstuffs enters the blood and is capable of binding to melatonin binding sites in the brain of mammals.
Biochem Mol Biol Int 1995 Mar
PMID:Identification of melatonin in plants and its effects on plasma melatonin levels and binding to melatonin receptors in vertebrates. 777 97

Melatonin is synthesized from serotonin by the enzymes serotonin N-acetyltransferase (SNAT) and hydroxyindole-O-methyl-transferase (HIOMT). We have previously reported that C57BL/6 mice do not have SNAT activity because of a mutation in an autosomal gene which is responsible for the absence of normal SNAT activity. In the present study, we have tried to map the loci of Nat-2 (the locus controlling SNAT activity) on chromosomes using a set of the BxH recombinant inbred strains which were derived from an initial cross between C3H/He with SNAT and C57BL/6 without the enzyme. Based on strain distribution patterns (SDPs), a close linkage on chromosome 11 was found between Nat-2, Es-3 (esterase-3), Glk (the locus controlling galactokinase activity) and Myla (myosin alkali light chains expressed in cardiac atrial muscle). The linkage between Nat-2 and Es-3 was confirmed by a conventional linkage test and the recombination frequency between these loci was estimated to be 16.1 +/- 3.6% (mean +/- S.E.M.).
Brain Res Mol Brain Res 1994 Feb
PMID:The locus controlling pineal serotonin N-acetyltransferase activity (Nat-2) is located on mouse chromosome 11. 817 Mar 56

The potential role of phospholipases in mediating melatonin-dependent inhibition of adenylyl cyclase was investigated in pars tuberalis (PT) cultures. The phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA) stimulated the release of choline metabolites and increased the transphosphatidylation reaction. The calcium ionophore A23187 stimulated the release of arachidonic acid from cultures. These observations demonstrate phospholipase A and D activities within PT. Phosphatidic acid inhibited forskolin-stimulated production of cyclic AMP both in PT cells and in membrane preparations. This indicates that melatonin could inhibit adenylyl cyclase by increasing phosphatidic acid levels through activation of cellular phospholipases. Melatonin did not stimulate the release of arachidonic acid or choline from PT cultures, nor did it increase intracellular levels of hydrophobic second messengers or stimulate transphosphatidylation. Therefore melatonin does not stimulate phospholipase A and D pathways in PT cells. However, these pathways are present in the PT and their activation could potentially modulate the cellular actions of melatonin.
Mol Cell Endocrinol 1994 Feb
PMID:Phospholipases and melatonin signal transduction in the ovine pars tuberalis. 818 63

Melatonin (N-acetyl-5-methoxytryptamine) was identified in the head and hemolymph of the silkworm, Bombyx mori, using reversed-phase high-performance liquid chromatography coupled with fluorometric detection and radioimmunoassay. In addition, evidence of arylakylamine (serotonin) N-acetyltransferase (NAT) a key enzyme controlling the synthesis of melatonin in vertebrates, was found in the head of the silkworm. Melatonin levels in the head and hemolymph and the NAT activity in the head were significantly higher during the dark period than during the light period of a 12-h light/12-h dark cycle. The day-night changes persisted in constant darkness but were suppressed by constant light. The results suggest that the synthesis and release of melatonin in the silkworm head occur as a circadian rhythm that is entrained by environmental light/dark cycles, as it is in the pineal gland of vertebrates. Melatonin in the silkworm head may function as a neurochemical mediator of photoperiodic control of developmental events such as molting, eclosion and diapause.
Mol Cell Endocrinol 1995 Nov 30
PMID:Melatonin and arylalkylamine N-acetyltransferase activity in the silkworm, Bombyx mori. 867 65

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.
Mol Pharmacol 1996 Jul
PMID:Characterization and regulation of the human ML1A melatonin receptor stably expressed in Chinese hamster ovary cells. 870 Jan 9

The ability of melatonin to influence lipopolysaccharide (LPS)-induced genotoxicity was tested using micronuclei as an index in both bone marrow and peripheral blood cells of rats. LPS was given as a single dose of 10 mg/kg. Melatonin (5 mg/kg) was injected prior to LPS administration and thereafter at 6 h intervals to the conclusion of the study (72 h). The number of micronucleated polychromatic erythrocytes increased significantly after LPS administration both in cells from peripheral blood and bone marrow. Melatonin administration to LPS-treated rats highly significantly reduced micronuclei formation in both peripheral blood and bone marrow cells beginning at 24 h after LPS administration and continuing to the end of the study. In blood the increase in micronuclei formation was time-dependent in LPS-treated rats with peak values being reached at 36-48 h. The ability of melatonin to reduce LPS-related genotoxicity is likely related to its antioxidant activity.
Mol Cell Endocrinol 1996 Mar 25
PMID:Lipopolysaccharide-induced DNA damage is greatly reduced in rats treated with the pineal hormone melatonin. 873 78

Rhodospirillum rubrum is a spiral anoxygenic photosynthetic bacterium that can exist under either aerobic or anaerobic conditions. The organism thrives in the presence of light or complete darkness and represents one of the oldest species of living organisms, possibly 2-3.5 billion years old. The success of this prokaryotic species may be attributed to the evolution of certain indole compounds that offer protection against life-threatening oxygen radicals produced by an evolutionary harsh environment. Melatonin, N-acetyl-5-methoxytryptamine, is an indolic highly conserved molecule that exists in protists, plants, and animals. This study was undertaken to determine the presence of an immunoreactive melatonin in the kingdom Monera and particularly in the photosynthetic bacterium, R. rubrum, under conditions of prolonged darkness or prolonged light. Immunoreactive melatonin was measured during both the extended day and extended night. Significantly more melatonin was observed during the scotophase than the photophase. This study marks the first demonstration of melatonin in a bacterium. The high level of melatonin observed in bacteria may provide on-site protection of bacterial DNA against free radical attack.
Cell Mol Biol Res 1995
PMID:Melatonin immunoreactivity in the photosynthetic prokaryote Rhodospirillum rubrum: implications for an ancient antioxidant system. 886 86

In ovine pars tuberalis cells which express high affinity Mel 1a melatonin receptors, the ability of melatonin to directly stimulate or inhibit AP-1 transcription factor gene expression was studied. Effects of melatonin upon mRNA expression by forskolin, serum and IGF-1 were also investigated. Northern analysis showed melatonin had no direct stimulatory nor inhibitory effect upon transcription or translation. Melatonin was able to significantly inhibit forskolin-stimulated induction of c-fos and jun B mRNA whilst forskolin had no effect upon c-jun or jun D. Induction of c-Fos translation by forskolin was also inhibited by melatonin. Serum induced c-fos and c-jun, but melatonin was unable to affect these changes. Similarly IGF-1 stimulated c-fos and melatonin had no effect upon this induction. From these results it can be concluded that melatonin has no independent effects on expression of the AP-1 genes, rather its primary function is to inhibit cell activities through cyclic AMP-dependent routes of gene activation.
Mol Cell Endocrinol 1996 Oct 14
PMID:Melatonin suppresses the induction of AP-1 transcription factor components in the pars tuberalis of the pituitary. 891 13

The pineal hormone melatonin modulates constitutive protein secretion from murine melanoma M2R cells in vitro, in a cholera-toxin (CTX)-sensitive process, without effecting major changes in cAMP. The effects of melatonin on GTP binding proteins and putative CTX substrates in these cells were investigated. Melatonin enhanced GTP gamma 35S binding and the incorporation of 32P-P3-(4-azidoanilido)-P1-5'-guanosine triphosphate (Az-32P-GTP) into 94, 40 and 28 kilodalton proteins. Similar changes were induced by CTX treatment. In addition, melatonin enhanced ADP ribosylation of several proteins, among them 94 and 40 kilodalton bands, apparently at arginyl residues. CTX catalyzed the ADP ribosylation of 45 and 40 (both recognized by antibodies specific to the C-terminal peptide of the Gs alpha subunit) and 94 kilodalton proteins and attenuated melatonin's effect. The melatonin-mediated ADP ribosylation reactions were attenuated by nicotinamide which inhibits mono(ADP ribosyl)transferases and poly(ADP-ribose)synthetase, but not by 3-amino benzamide, a specific inhibitor of poly(ADP-ribose)synthetase. Nicotinamide but not 3-amino benzamide prevented the enhancement by melatonin of GTP gamma 35S binding. These results indicate that melatonin enhances protein ADP ribosylation and consequently GTP exchange in a number of CTX-sensitive G proteins. They demonstrate a novel route for concerted activation of multiple GTP binding proteins by a single hormone.
Mol Cell Endocrinol 1996 Oct 30
PMID:Enhancement by melatonin of GTP exchange and ADP ribosylation reactions. 896 Dec 51


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