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  • 1
    Electronic Resource
    Electronic Resource
    Molecular determinants for the differential coupling of Gα16 to the melatonin MT1, MT2 and Xenopus Mel1c receptors (2002)
    Oxford, UK : Blackwell Science, Ltd
    Journal of neurochemistry 80 (2002), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: The pineal neurohormone melatonin modulates a variety of physiological processes through different receptors. It has recently been reported that the cloned melatonin receptors (MT1, MT2 and Mel1c) exhibit differential abilities to stimulate phospholipase C (PLC) via G16. Here we examined the molecular basis of such differences in melatonin receptor signaling. Coexpression of MT1 or MT2 with the α subunit of G16 (Gα16) allowed COS-7 cells to accumulate inositol phosphates in response to 2-iodomelatonin. In contrast, Mel1c did not activate Gα16 even though its expression was demonstrated by radioligand binding and agonist-induced inhibition of adenylyl cyclase. As Mel1c possesses an exceptionally large C-terminal tail, we further asked if this structural feature prevented productive coupling to Gα16. Eleven chimeric melatonin or mutant receptors were constructed by swapping all or part of the C-terminal tail between MT1, MT2 and Mel1c. All chimeras were fully capable of binding 2-[125I]iodomelatonin and inhibiting adenylyl cyclase. Chimeras containing the full-length Mel1c tail were incapable of activating Gα16, while those that contained the complete C-terminal region of either MT1 or MT2 stimulated PLC. Incorporation of the extra portion of the C-terminal tail of Mel1c to either MT1 or MT2 completely abolished the chimeras' ability to stimulate PLC via Gα16. In contrast, trunc- ation of the C-terminal tail of Mel1c allowed interaction with Gα16. Our results suggest that Gα16 can discern structural differences amid the three melatonin receptors and provide evidence for functional distinction of Mel1c from MT1 and MT2 receptors.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.0022-3042.2002.00767.x
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  • 2
    Electronic Resource
    Electronic Resource
    Differential inhibitory effects of melatonin analogs and three naphthalenic ligands on 2-[125I]iodomelatonin binding to chicken tissues (1997)
    Oxford, UK : Blackwell Publishing Ltd
    Journal of pineal research 23 (1997), S. 0 
    Details
    ISSN: 1600-079X
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Pang CS, Tang PL, Song Y, Pang SF, Ng KW, Guardiola-Lemaitre B, Delagrange P, Brown G.M. Differential inhibitory effects of melatonin analogs and three naphthalenic ligands on 2-[l25I]iodomelatonin binding to chicken tissues. J. Peneal Res. 1997; 23:148–155. © Munksgaard, Copenhagen〈section xml:id="abs1-1"〉〈title type="main"〉AbstractWe have compared the 50% inhibition values of 2-[l25I]iodomelatonin ([125I]Mel) competition curves by melatonin and 3 naphthalenic ligands, N-[2-(7-methoxy-l-naphthyl) ethyl] cyclobutane carboxamide (S20642), N-propyl N-[2-(7-methoxy-l-naphtyl) ethyl] urea (S20753), and N-[2-(7-methoxy-l-naphthyl) ethyl] crotonamide (S20750), using membrane preparations of four tissues (lung, spleen, brain, and kidney) of the chicken simultaneously. In retired breeders, we have demonstrated that the affinities of S20642 were similar in the lung and spleen. However they were 2-fold lower in the brain and 80-fold lower in the kidney. Similar differential binding affinities to the melatonin receptors were observed in the four tissues of young male chicks. This suggests that age and sex have little influence on the differential inhibitory properties of melatonin and S20642 in the tissues studied. The addition of guanosine 5'-0-thiotriphosphate (GTPyS), which encouraged the uncoupling of melatonin receptor to the G protein complex, lowered the binding affinity of melatonin and S20642 in the tissues studied but their differentia] affinities in the four tissues were however maintained. The affinities of 5-methoxy-N-cyclopropanoyltryptamine (CPMT) in the kidney were also 5–10-fold lower than those in the lung, spleen, and brain of young male chicks. The distinctive differential affinities of melatonin, S20642, and CPMT for [l25I]Mel binding sites in the chicken lung, spleen, brain, and kidney indicated that the binding sites in these tissues are heterogeneous. Our study implicated that the naphthalenic ligand S20642 may be a useful melatonin analog to distinguish melatonin receptor subtypes in tissues and a possible drug candidate worthwhile for further investigations.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1600-079X.1997.tb00348.x
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  • 3
    Electronic Resource
    Electronic Resource
    2[125I]Iodomelatonin binding sites in guinea pig platelets (2002)
    Oxford UK : Blackwell Publishing Ltd.
    Journal of pineal research 32 (2002), S. 0 
    Details
    ISSN: 1600-079X
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Using 2[125I]iodomelatonin as the radioligand, we characterized 2[125I]iodomelatonin binding sites in guinea pig platelet membrane preparations. Saturation radioreceptor studies indicated that these 2[125I]iodomelatonin binding sites were of picomolar affinity and femtomolar density. The dissociation constant (Kd) and maximum number of receptor sites (Bmax) were 42.5 ± 1.79 pM and 11.8 ± 0.8 fmol/mg protein (n=6), respectively. 2[125I]Iodomelatonin competition studies with indoles or drugs indicate the following rank order of potency: 2-iodomelatonin 〉melatonin ≥ 6-chloromelatonin 〉 6-hydroxymelatonin 〉 N-acetylserotonin 〉  5-methoxytryptophol, whereas serotonin and its analogs had less than 20% inhibition at 0.1 mM. Guanosine 5′-O-(3-thiotriphosphate) significantly increased the Kd by twofold suggesting that these binding sites are coupled to the guanine nucleotide binding proteins. Immunoblotting studies using anti-MT1 IgG demonstrated one peptide blockable band with an apparent molecular mass of 37 kDa. Melatonin had no effect on prostacyclin or forskolin-stimulated intracellular 3′,5′-cyclic adenosine monophosphate accumulation. A diurnal variation in binding density, which was abolished after the animals were adapted to constant light conditions, was observed. Age related studies demonstrated that Bmax increased as the animal matured. Physiological melatonin concentrations potentiated whereas those at pharmacological levels inhibited adenosine diphosphate- or arachidonic acid-stimulated platelet aggregation. Our study demonstrated G-protein coupled, saturable, reversible and highly specific picomolar affinity 2[125I]iodomelatonin binding sites in guinea pig platelets. Pharmocological and physiological data indicate that they may be different from the nanomolar [3H]melatonin binding sites in human platelets previously reported.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1034/j.1600-079x.2002.1822.x
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  • 4
    Electronic Resource
    Electronic Resource
    Chimeric Gαq subunits can distinguish the long form of the Xenopus Mel1c melatonin receptor from the mammalian mt1 and MT2 melatonin receptors (2001)
    Copenhagen : Munksgaard International Publishers
    Journal of pineal research 30 (2001), S. 0 
    Details
    ISSN: 1600-079X
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: The family of melatonin receptors is composed of the mt1, MT2, and Mel1c subtypes. The Mel1c is further divided into one long and two short isoforms. A recent study has shown that, unlike mt1 and MT2, the long form of Mel1c is incapable of activating the pertussis toxin-insensitive G16. Here we used three well-characterized Gαq chimeras to explore the coupling specificity of the melatonin receptors. The qi5, qo5, and qz5 chimeras can link numerous Gi-coupled receptors to the stimulation of phosphoinositide-specific phospholipase C. Both mt1 and MT2 receptors interacted productively with the Gαq chimeras, while the long form of Mel1c was totally ineffective. Among the Gαq chimeras, qo5 was less efficiently coupled to the melatonin receptors. Such differential coupling is best explained by structural differences between the melatonin receptors as well as among the Gαq chimeras. Since the long form of Mel1c receptor possesses an exceptionally large C-terminal tail, we tested the ability of four melatonin receptor C-terminal tail chimeras (Chi 1–4) to interact with the Gαq chimeras. The presence of the large C-terminal tail of Mel1c in Chi 1 and Chi 3 markedly hindered their coupling to the Gαq chimeras. On the other hand, the attachment of either the mt1 or MT2 C-terminal tail to a Mel1c backbone produced chimeras (Chi 2 and Chi 4) that were capable of activating the Gαq chimeras. These findings suggest the involvement of C-terminal regions of melatonin receptors in the recognition of G proteins.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1034/j.1600-079X.2001.300306.x
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  • 5
    Electronic Resource
    Electronic Resource
    2[125I]Iodomelatonin binding and interaction with β-adrenergic signaling in chick heart/coronary artery physiology (2002)
    Oxford UK : Munksgaard International Publishers
    Journal of pineal research 32 (2002), S. 0 
    Details
    ISSN: 1600-079X
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: 2[125I]Iodomelatonin ([125I]Mel) binding sites were characterized on membrane preparations of young chick hearts. [125I]Mel binding was rapid, saturable, stable, reversible, specific and of picomolar affinity and femtomolar density. Guanosine 5′-O-(3-thiotriphosphate) significantly lowered the binding affinity by one- to twofold, supporting G-protein linkage of melatonin receptors. Binding was detected as early as embryonic day-9 (E9), and increased steadily peaking at E13 before it slowly declined to about 15% of the peak level a week posthatch. Specific [125I]Mel binding was significantly increased by in ovo administration of inotropic agents dopamine and isoproterenol. Melatonin or 2-iodo-N-butanoyl-tryptamine inhibited isoproterenol-stimulated cAMP accumulation in primary heart cell cultures and the effect was attenuated after pretreatment with pertussis toxin (PTX). Localization of melatonin receptors using autoradiography showed intense labeling in the coronary arteries in all age groups whereas those in the myoblasts decreased as the heart matured. While the myoblasts and undifferentiated developing coronary arteries expressed melatonin MT1 receptor subtype in E11 hearts as detected by immunostaining with anti-MT1 receptor serum, immunoreactivities were observed mostly on the endothelium/subendothelium and smooth muscle cells of the well developed coronary vessels in posthatch hearts. Collectively, our data suggest the presence of PTX-sensitive, G protein-coupled melatonin receptors, whose expression is up-regulated by dopamine and isoproterenol, in the chick heart. Activation of these receptors, which include MT1 subtype, may modulate β-adrenergic receptor-mediated cAMP signaling in the control of chick heart and coronary artery physiology.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1034/j.1600-079X.2002.01860.x
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  • 6
    Electronic Resource
    Electronic Resource
    Melatonin-induced inhibition of proliferation and G1/S cell cycle transition delay of human choriocarcinoma JAr cells: Possible involvement of MT2 (MEL1B) receptor (1999)
    Oxford, UK : Blackwell Publishing Ltd
    Journal of pineal research 27 (1999), S. 0 
    Details
    ISSN: 1600-079X
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: Melatonin, the pineal neurohormone, is an evolutionarily conserved photoperiodic signaling molecule with diverse functions that include the entrainment of human circadian rhythms. Although evidence supporting a direct inhibitory action of melatonin on human cancer cell proliferation exists in the literature, the molecular and cellular signaling mechanisms involved are largely undefined. In our study, significant inhibition of human choriocarcinoma JAr cell proliferation at physiological and pharmacological concentrations of melatonin was observed. 2-Iodomelatonin, a high affinity melatonin receptor agonist, was more potent than melatonin in inhibiting JAr cell proliferation. In addition, the presence of putative melatonin receptors in choriocarcinoma was suggested by the demonstration of specific 2-[125I]iodomelatonin binding to the tumor. Interestingly, the selective MT2 melatonin receptor ligand, 4-phenyl-2-propionamidotetraline (4-P-PDOT), was found to exert not only concentration-dependent anti-proliferative actions on JAr cells, but also additive effects with melatonin in inhibiting JAr cell proliferation. Furthermore, MT2 melatonin receptor gene expression by JAr cells was demonstrated by reverse transcription-polymerase chain reaction (RT-PCR) and in situ hybridization (ISH). Taken together, our data suggest that the reported anti-proliferative action of melatonin on human choriocarcinoma JAr cells may be mediated, in part, by MT2 melatonin receptor. Moreover, analysis of melatonin effect on cell cycle kinetics indicated that G1/S transition delay may underlie the observed inhibition of choriocarcinoma cell proliferation by melatonin.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1600-079X.1999.tb00614.x
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