UMLS:C0043167 - FACTA Search

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

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

Melatonin, a pineal hormone that induces sleep, has become a popular over-the-counter drug. The cellular effects of melatonin, however, are only beginning to be studied. We have recently shown that stimulation of the MT1 melatonin receptor induces rapid and dramatic cytoskeletal rearrangements in transformed non-neuronal cells (Witt-Enderby et al., Cell. Motil. Cytoskel. 46 (2000) 28). These cytoskeletal changes result in the formation of structures that closely resemble neurites. In this work, we show that the N1E-115 mouse neuroblastoma cell line rapidly responds to melatonin stimulation and forms neurites within 24 h. We also demonstrate that these cells readily bind 2-[125I]iodomelatonin at levels consistent with what is noted for native tissues (B(max)=3.43+/-1.56 fmol/mg protein; K(d)=240 pM). Western analysis shows that these cells possess and express melatonin receptors of the MT1 subtype. Treatment with pertussis toxin eliminates neurite formation whereas treatment with the MT2 subtype-specific activator, BMNEP, does not induce neurite formation. We have previously shown that increases in MEK 1/2 and ERK 1/2 phosphorylation are correlated with the shape changes in transformed CHO cells. Western analysis of the MEK/ERK signaling pathway in N1E-115 cells shows that this pathway is most likely maximally and constitutively stimulated. This may account for the spontaneous production of neurites noted for this cell line after long culture periods. The results of this work show that melatonin receptor stimulation in a neuronal cell type results in the formation of neurites and that the receptors responsible for melatonin-induced neurite formation in N1E-115 cells are most likely of the MT1 subtype.
...
PMID:N1E-115 mouse neuroblastoma cells express MT1 melatonin receptors and produce neurites in response to melatonin. 1134 73

Melatonin inhibits fatty acid uptake and linoleic acid-dependent growth in hepatoma 7288CTC in vivo in Buffalo rats. In this study we measured the effects of melatonin on arteriovenous differences for fatty acids across inguinal fat pads in fed and fasted rats to determine if fatty acid transport in white adipose tissue was also affected by melatonin. Intravenous infusion of melatonin in fasted tumor-bearing rats in vivo simultaneously and rapidly inhibited both fatty acid release from fat pads and fatty acid uptake by the tumors. Perfusion of fat pads in situ in normal rats with melatonin (0.1 nM) inhibited fatty acid release (fasted rats) and uptake (fed rats). Fatty acid transport was restored by addition of any of the following: a melatonin receptor antagonist (S 20928, 1.0 nM), pertussis toxin (0.5 microg/ml), forskolin (1 microM) or 8-Br-cAMP (10 microM). We conclude that fatty acid transport in inguinal fat pads requires cAMP and that melatonin inhibits this transport via a melatonin receptor-mediated, Gi protein-coupled signal transduction pathway. Melatonin has both anticachectic and lipid homeostatic actions in the white adipose tissue of inguinal fat pads.
...
PMID:Melatonin inhibits fatty acid transport in inguinal fat pads of hepatoma 7288CTC-bearing and normal Buffalo rats via receptor-mediated signal transduction. 1143 49

Melatonin is a pineal hormone that regulates seasonal reproduction and has been used to treat circadian rhythm disorders. The melatonin 1a receptor is a seven- transmembrane domain receptor that signals predominately via pertussis toxin-sensitive G-proteins. Point mutations were created at residue N124 in cytoplasmic domain II of the receptor and the mutant receptors were expressed in a neurohormonal cell line. The acidic N124D- and E-substituted receptors had high-affinity (125)I-melatonin binding and a subcellular localization similar to the neutral N124N wild-type receptor. Melatonin efficacy for the inhibition of cAMP by N124D and E mutations was significantly decreased. N124D and E mutations strongly compromised melatonin efficacy and potency for inhibition of K(+)-induced intracellular Ca(++) fluxes and eliminated control of spontaneous calcium fluxes. However, these substitutions did not appear to affect activation of Kir3 potassium channels. The hydrophobic N124L and N124A or basic N124K mutations failed to bind (125)I-melatonin and appeared to aggregate or traffic improperly. N124A and N124K receptors were retained in the Golgi. Therefore, mutants at N124 separated into two sets: the first bound (125)I-melatonin with high affinity and trafficked normally, but with reduced inhibitory coupling to adenylyl cyclase and Ca(++) channels. The second set lacked melatonin binding and exhibited severe trafficking defects. In summary, asparagine-124 controls melatonin receptor function as evidenced by changes in melatonin binding, control of cAMP levels, and regulation of ion channel activity. Asparagine-124 also has a unique structural effect controlling receptor distribution within the cell.
...
PMID:Regulation of melatonin 1a receptor signaling and trafficking by asparagine-124. 1146 55

Because the pineal hormone melatonin has been implicated in affecting adiposity in rats and fatty acid transport in certain rat tumor models, we tested whether melatonin regulates lipolysis in a normal cell system in vitro. Adipocytes were isolated from the inguinal fat pads (i.e. sc fat) of Sprague Dawley male rats during mid-light phase. Lipolysis was stimulated with isoproterenol (3 microM), and cells were incubated for 4 h in the presence or absence of a physiological circulating concentration of melatonin (1 nM). Lipolysis was measured by determining the amount of glycerol present in the incubation buffer, expressed as nmol glycerol/mg cellular fatty acid. We observed a 20- to 30-fold stimulation of basal lipolysis by isoproterenol, and this stimulation was inhibited 50--70% by melatonin. Melatonin exhibited this effect over a wide range of concentrations tested (100 pM-1 microM) with an IC(50) of approximately 500 pM. The effect by melatonin (1 nM) was completely blocked by pertussis toxin (50 ng/ml), by 8-bromo-cAMP (10 nM), and by the melatonin receptor antagonist S-20928 (1 nM). These results suggest that the antilipolytic effect occurs through one of the G(i) protein-coupled melatonin receptors because we have shown that both the mt(1) (Mel 1a) and MT(2) (Mel 1b) melatonin receptors are expressed in inguinal adipocytes. Melatonin inhibition of lipolysis was not observed in adipocytes isolated from rat epididymal fat pads (i.e. visceral fat), even though these cells also express both the mt(1) and MT(2) receptors. The results indicate that physiological circulating concentrations of melatonin inhibit isoproterenol-induced lipolysis in rat adipocytes via a G protein-coupled melatonin receptor-mediated signal transduction pathway in a site-specific manner.
...
PMID:Inhibition of isoproterenol-induced lipolysis in rat inguinal adipocytes in vitro by physiological melatonin via a receptor-mediated mechanism. 1151 54

It has been shown that melatonin regulates uterine function. Our previous studies have demonstrated the presence of melatonin receptors in the rat uterine endometrium, indicating that melatonin may act directly on the uterus. In the present study, the histological localization of the rat uterine melatonin binding was revealed by autoradiography and the molecular subtyping was studied by in situ hybridization in the stromal cells. The signal transduction process and effects of melatonin on stromal cell proliferation was also investigated. Our autoradiograms showed that 2[(125)I]iodomelatonin binding sites were localized in the antimesometrial endometrial stroma. In situ hybridization with specific mt(1) receptor cDNA probe in the primary culture of antimesometrial stromal cells demonstrated the expression of mt(1) receptor mRNAs. Melatonin dose-dependently inhibited forskolin-stimulated cAMP accumulation, which was reversed by pertussis toxin. This indicates that the rat uterine melatonin receptors are negatively coupled to adenylate cyclase via pertussis toxin sensitive G(i) protein. Melatonin also inhibited the incorporation of [(3)H]thymidine in the rat uterine antimesometrial stromal cells, showing that melatonin has an anti-proliferative effect on the uterus. Our results suggest that melatonin may act directly on the mt(1) melatonin receptors in the rat uterine antimesometrial stromal cells to inhibit their proliferation. Its action may be mediated through a pertussis toxin-sensitive adenylate cyclase coupled G(i)-protein.
...
PMID:mt(1) Receptor-mediated antiproliferative effects of melatonin on the rat uterine antimesometrial stromal cells. 1180 54

Melatonin is a pineal hormone involved in neuroendocrine processes in mammals. It has been shown that melatonin inhibits the enzymatic activities of adenylyl cyclases and the transcriptional activities of CREB. In this report, we demonstrate that 2-iodomelatonin (2IMT) treatment on COS-7 cells transfected with melatonin receptors (mt1 and MT2) induces c-Jun N-terminal kinase (JNK) activation, which is pertussis toxin (PTX)-sensitive, Ras/Rac-dependent and may involve Src-family protein tyrosine kinases. Moreover, PTX-insensitive Gs, Gz and G16 are capable of linking activated melatonin receptors to the stimulation of JNK. Agonist stimulation on PTX-pretreated COS-7 cells overexpressing mt1 receptor, Galpha(s) and adenylyl cyclase VI led to increased cAMP accumulation. Stimulation of endogenous mt1 receptors in MCF-7 cells was associated with the activation of both JNK and extracellular signal-regulated kinase (ERK). This report demonstrates the stimulatory effect of melatonin receptors on JNK, and provides experimental evidence for a functional coupling between the G(i)-coupled melatonin receptor and Gs, in terms of adenylyl cyclase activation.
...
PMID:Melatonin mt1 and MT2 receptors stimulate c-Jun N-terminal kinase via pertussis toxin-sensitive and -insensitive G proteins. 1181 53

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 beta-adrenergic receptor-mediated cAMP signaling in the control of chick heart and coronary artery physiology.
...
PMID:2[125I]Iodomelatonin binding and interaction with beta-adrenergic signaling in chick heart/coronary artery physiology. 1198 94

Melatonin receptors interact with pertussis toxin-sensitive G proteins to inhibit adenylate cyclase. However, the G protein coupling profiles of melatonin receptor subtypes have not been fully characterised and alternative G protein coupling is evident. The five C-terminal residues of Galpha subunits confer coupling specificity to G protein-coupled receptors. This report outlines the use of Galphas chimaeras to alter the signal output of human melatonin receptors and investigate their interaction with the C-termini of Galpha subunits. The Galphas portion of the chimaeras confers the ability to activate adenylate cyclase leading to cyclic AMP production. Co-transfection of HEK293 cells expressing MT(1) or MT(2) melatonin receptors with Galphas chimaeras and a cyclic AMP activated luciferase construct provided a convenient and sensitive assay system for identification of receptor recognition of Galpha C-termini. Luciferase assay sensitivity was compared with measurement of cyclic AMP elevations by radioimmunoassay. Differential interactions of the melatonin receptor subtypes with Galpha chimaeras were observed. Temporal and kinetic parameters of cyclic AMP responses measured by cyclic AMP radioimmunoassay varied depending on the Galphas chimaeras coupled. Recognition of the C-terminal five amino acids of the Galpha subunit is a requisite for coupling to a receptor, but it is not the sole determinant.
...
PMID:Differential coupling of the extreme C-terminus of G protein alpha subunits to the G protein-coupled melatonin receptors. 1237 82

Melatonin, a pineal hormone, modifies numerous physiologic processes including circadian rhythms and sleep. In specific tissues, melatonin appears to have an inverse relationship with dopamine. To examine this relationship, a pheochromocytoma cell line (PC12) was used to determine the extent of melatonin's ability to inhibit nicotine-stimulated dopamine release. Multiple experiments were conducted that examined: (1). the dose response of acute melatonin (5 min); (2). the effects of chronic melatonin (16 h pre-exposure); (3). the effects of prior nicotine or melatonin exposure (5 min) on melatonin's ability to alter dopamine release from a second 5-min nicotine exposure; and (4). the role of melatonin receptors (by pertussis toxin inhibition) on nicotine-stimulated dopamine release. In the dose response studies, melatonin inhibited nicotine-stimulated dopamine release with an ED50 of 8.6 microM. Chronic exposure to melatonin had no effect on melatonin's acute inhibition of nicotine-stimulated dopamine release. Prior nicotine or melatonin exposure had little effect on subsequent melatonin or nicotine exposure, except that the cells exposed to nicotine were not responsive to a second exposure to nicotine. Blockade of melatonin receptor function by pre-exposure to pertussis toxin (16 h) did not prevent melatonin's inhibition of nicotine-stimulated dopamine release. However, the toxin-treated cells were less inhibited by melatonin when compared to control cells suggesting a partial role for melatonin receptors. These results indicate that melatonin can acutely inhibit nicotine-stimulated dopamine release in PC12 cells. This model system allows detailed examination of melatonin's cellular actions as well as supporting a role for melatonin on neuronal dopamine release.
...
PMID:Melatonin inhibition of nicotine-stimulated dopamine release in PC12 cells. 1264 12

The sweeteners saccharin, D-tryptophan, and neohesperidin dihydrochalcone (NHD) and the bitter tastant cyclo(Leu-Trp) stimulated concentration-dependent pigment aggregation in a Xenopus laevis melanophore cell line similar to melatonin. Like melatonin, these tastants inhibited (by 45-92%) cAMP formation in melanophores; pertussis toxin pretreatment almost completely abolished the tastant-induced cAMP inhibition, suggesting the involvement of the inhibitory pathway (Gi) of adenylyl cyclase. The presence of luzindole (melatonin receptor antagonist) almost completely abolished the inhibition of cAMP formation induced by saccharin, D-tryptophan, and cyclo(Leu-Trp) but only slightly affected the inhibitory effect of NHD. In contrast, the presence of an alpha2-adrenergic receptor antagonist, yohimbine, almost completely abolished the inhibition of cAMP formation induced by NHD but had only a minor effect on that induced by the other tastants. Thus saccharin, D-tryptophan, and cyclo(Leu-Trp) are melatonin receptor agonists whereas NHD is an alpha2-adrenergic receptor agonist, but both pathways lead to the same transduction output and cellular response. Formation of D-myo-inositol 1,4,5-trisphosphate (IP3) in melanophores was reduced (15-58%, no concentration dependence) by saccharin, D-tryptophan, and cyclo(Leu-Trp) stimulation but increased by NHD stimulation. Tastant stimulation did not affect cGMP. Although some of the above tastants were found to be membrane permeant, their direct activation of downstream transduction components in this experimental system is questionable. MT1 and MT2 melatonin receptor mRNAs were identified in rat circumvallate papilla taste buds and nonsensory epithelium, suggesting the occurrence of MT1 and MT2 receptors in these tissues. Melatonin stimulation reduced the cellular content of cAMP in taste cells, which may or may not be related to taste sensation.
...
PMID:Some sweet and bitter tastants stimulate inhibitory pathway of adenylyl cyclase via melatonin and alpha 2-adrenergic receptors in Xenopus laevis melanophores. 1283 35

<< Previous 1 2 3 4 5 6 7 8 Next >>