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At least 19 recordsLinked to original sources
PubMed1999

Melatonin receptors and melatonin inhibition of duck salt gland secretion.

Most of the NaCl ingested by marine birds is reabsorbed from renal filtrate and excreted by the cephalic salt glands as a hypertonic NaCl secretion (SGS). Ducks have salt glands and their kidney cells have melatonin receptors. Melatonin affects glomerular filtration rate and tubular uptake of sodium (Na(+)) in mammals. We hypothesized that (1) duck salt glands also have melatonin receptors and (2) melatonin affects extrarenal Na(+) secretion. Both hypotheses were accepted because putative melatonin receptors were identified by 2¿(125)Iĭodomelatonin binding in salt glands of Pekin ducks, Anas platyrhynchos, and because melatonin inhibited SGS in these ducks. Saline ingestion increased B(max), but not K(d), of salt gland receptors. The duration of NaCl infusion needed to stimulate SGS was positively related with preinfusion plasma melatonin concentration (¿mel(pl)). Raising ¿mel(pl) prior to NaCl infusion further delayed onset of secretion and decreased secretion rate and concentration without affecting plasma volume and Na(+) concentration. Abrupt increase in ¿mel(pl) during SGS immediately decreased the rate by 43%. Secretion rate remained lower than the control rate during the subsequent hour; secretion concentration was not affected. This is the first report of putative melatonin binding sites in avian salt glands. Melatonin slowed the onset of NaCl-induced salt gland secretion and decreased its rate.

Animals↗
PubMed2002

Differential coupling of the extreme C-terminus of G protein alpha subunits to the G protein-coupled melatonin receptors.

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.

Cell Line↗
PubMedDate not supplied

Polymorphism and signalling of melatonin receptors.

Melatonin receptors belong to the superfamily of G protein-coupled receptors. Cloning of Mel1c receptors expressed in Xenopus skin revealed the existence of a polymorphism for these receptors. Heterologous expression of the two allelic isoforms, called Mel1c(alpha) and Mel1c(beta), indicated functional differences in their signalling properties. Both isoforms are coupled to the cAMP and cGMP pathways. However, the alpha isoform is preferentially coupled to the cAMP pathway, whereas the beta isoform couples preferentially to the cGMP pathway. Coupling differences may be explained by the fact that five of the six amino acid substitutions between the two isoforms are localized within intracellular receptor regions potentially involved in G protein coupling. Allelic isoforms were also observed for Mel1a receptors expressed in ovine pars tuberalis, suggesting that polymorphism is a general feature of the melatonin receptor family. We also evaluated the potential of the two human melatonin receptor subtypes, Mel1a and Mel1b, to modulate the cGMP pathway. Melatonin inhibited intracellular cGMP levels in a dose-dependent manner in HEK293 cells transfected with the human Mel1b receptor. This was not the case for HEK293 cells transfected with the human Mel1a receptor. In conclusion, our results indicate that the expression of receptor subtypes and isoforms may permit differential signalling between melatonin receptors.

1-Methyl-3-isobutylxanthine↗
PubMed1998

[Structure and function of melatonin receptors].

Melatonin receptors belong to the super-family of G protein-coupled receptors. They modulate a large spectrum of physiological functions including regulation of circadian rhythms and seasonal reproduction. Pharmacological evidence suggests the expression of two types of receptors, called Mel1 and Mel2. So far, only Mel1 receptors have been cloned and classified into three subtypes (Mel1A, Mel1B, Mel1C). Mel1 receptors are expressed in the brain, the retina and several other peripheral tissues. All Mel1 subtypes show comparable pharmacological profiles including inhibition of adenylyl cyclase. Cloning and expression of two allelic isoforms of the Mel1 receptor from Xenopus laevis has revealed another signalling pathway, inhibition of cGMP levels via the soluble guanylyl cyclase pathway. The two isoforms are differentially coupled to the cAMP and cGMP pathways indicating the existence of functional differences between melatonin receptors. Future research topics will include cloning of the Mel2 receptor, receptor regulation and the elucidation of melatonin receptor's function in peripheral tissues.

Adenylyl Cyclases↗
PubMed1996

Serotonin and N-acetylserotonin effects on pigment cells of the toad Bufo ictericus: pharmacological characterization of melatonin receptors.

Melatonin is a skin lightening agonist of the toad Bufo ictericus. The hormone also exhibits an autodesensitizing action as well as an inhibitory activity on the darkening response to alpha-MSH. In an attempt to pharmacologically characterize the melatonin receptor of the toad pigment cells, serotonin and N-acetylserotonin (intermediate products of melatonin biosynthesis) biological activities were compared to melatonin effects. Serotonin (6.4 x 10(-5) to 10(-9) M) exhibited no lightening or inhibitory activity on MSH-elicited darkening responses or melatonin-elicited lightening responses. N-acetylserotonin, although less potent than melatonin, elicited a significant lightening response on previously MSH-darkened skins. Previous exposure of the skins with N-acetylserotonin reduced both MSH-induced darkening and melatonin-induced lightening in MSH-darkened skins. These results suggest a competitive inhibition of melatonin by N-acetylserotonin and indicate that melatonin receptors in B. ictericus pigment cells may be similar to ML-1 type found in chicken retina.

Animals↗
PubMedDate not supplied

[Signaling by melatonin receptors].

Melatonin is a hormone involved in various physiological processes such as the circadian cycle, hormone release and immune response. High-affinity melatonin receptors are classified in two pharmacologically distinct groups: Mel1 and Mel2. These receptors have first been localized in different organs and brain structures and some subtypes have since been cloned. Inhibition of adenylyl cyclase by Mel1 receptors is the best investigated signalling pathway but cannot be entirely responsible for the diversity of melatonin-induced phenomena. Phospholipase C, potassium ion channels and guanylyl cyclases have also been reported to be modulated by melatonin. This review updates present knowledge of the characterization and signalization of melatonin receptors.

Adenylyl Cyclase Inhibitors↗
PubMed2003

Mutagenesis studies of the human MT2 melatonin receptor.

Melatonin mediates its physiological effects through activation of high affinity G protein-coupled receptors. The vertebrate MT(1), MT(2) and Mel(1c) melatonin receptors are molecularly and pharmacologically distinct. Three molecular models of melatonin recognition for the MT(1) and/or Mel(1c) melatonin receptors have been proposed. To determine if these models applied to the MT(2) melatonin receptor, we mutated seven conserved residues to alanine in the hMT(2) melatonin receptor and expressed the receptors in HEK-293 cells. Competition of melatonin for 2-[125I]-iodomelatonin binding revealed that mutation of Asn 16 in TM4 or His 7 in TM5 of the hMT(2) melatonin receptor significantly decreased the binding affinity for melatonin when compared with wild-type. In addition, competition of 4P-ADOT, N-acetyltryptamine, luzindole, and 5-methoxytryptophol for 2-[125I]-iodomelatonin binding suggested Asn 16 in TM4 may facilitate binding of the 5-methoxy group of the melatonin molecule to the hMT(2) melatonin receptor. Trp 13 or Phe 6 in TM6 while not critical for melatonin binding, may interact with aromatic regions of luzindole and 4P-ADOT. Mutation of Ser 8 or Ser 12 in TM3, or Ser 6 in TM7 did not affect the affinity of melatonin for competition with 2-[125I]-iodomelatonin to the hMT(2) melatonin receptor, although equivalent serines (Ser 8 and Ser 12 in TM3) were reported to be critical for melatonin binding to the hMT(1) melatonin receptor. Thus these results are the first to identify residues within the transmembrane regions of the hMT(2) melatonin receptor critical for melatonin binding, highlighting potential structural differences between the MT(1) and MT(2) melatonin receptor binding pockets.

Amino Acid Sequence↗
PubMed2003

Molecular pharmacology, regulation and function of mammalian melatonin receptors.

Melatonin (5-methoxy-N-acetyltryptamine), dubbed the hormone of darkness, is released following a circadian rhythm with high levels at night. It provides circadian and seasonal timing cues through activation of G protein-coupled receptors (GPCRs) in target tissues (1). The discovery of selective melatonin receptor ligands and the creation of mice with targeted disruption of melatonin receptor genes are valuable tools to investigate the localization and functional roles of the receptors in native systems. Here we describe the pharmacological characteristics of melatonin receptor ligands and their various efficacies (agonist, antagonist, or inverse agonist), which can vary depending on tissue and cellular milieu. We also review melatonin-mediated responses through activation of melatonin receptors (MT1, MT2, and MT3) highlighting their involvement in modulation of CNS, hypothalamic-hypophyseal-gonadal axis, cardiovascular, and immune functions. For example, activation of the MT1 melatonin receptor inhibits neuronal firing rate in the suprachiasmatic nucleus (SCN) and prolactin secretion from the pars tuberalis and induces vasoconstriction. Activation of the MT2 melatonin receptor phase shifts circadian rhythms generated within the SCN, inhibits dopamine release in the retina, induces vasodilation, enhances splenocyte proliferation and inhibits leukocyte rolling in the microvasculature. Activation of the MT3 melatonin receptor reduces intraocular pressure and inhibits leukotriene B4-induced leukocyte adhesion. We conclude that an accurate characterization of melatonin receptors mediating specific functions in native tissues can only be made using receptor specific ligands, with the understanding that receptor ligands may change efficacy in both native tissues and heterologous expression systems.

Animals↗
PubMed2000

Melatonin induction of filamentous structures in non-neuronal cells that is dependent on expression of the human mt1 melatonin receptor.

Melatonin has gained recent popularity as a treatment for insomnia and other sleep disorders; however, its cellular effects are unknown. We report the effects of melatonin on the cellular morphology of Chinese hamster ovary (CHO) cells transformed to express the human melatonin receptors, mt1 and MT2. Our results show that melatonin exerts a strong influence on cellular shape and cytoskeletal organization in a receptor-dependent and possibly subtype-selective manner. The cell shape change that we see after a 5-h treatment of these non-neuronal cells with a pharmacological concentration of melatonin consists of the formation of long filamentous outgrowths that are reminiscent of the neurite processes produced by differentiating nerve cells. This morphological change occurs exclusively in cells expressing the mt1 receptor. We find that the microtubule and microfilament organization within these outgrowths is similar to that of neurites. Microtubules are required for the shape change to occur as Colcemid added in combination with melatonin completely blocks outgrowth formation. We demonstrate that the number of cells showing the altered cell shape is dependent on melatonin concentration, constant exposure to melatonin and that outgrowth frequencies increase when protein kinase A (PKA) is inhibited. Concomitant melatonin-dependent increases in MEK 1/2 and ERK 1/2 phosphorylation are noted in mt1-CHO cells only. The production of filamentous outgrowths is dependent on the translation of new protein but not the transcription of new mRNA. Outgrowth number is not controlled by centrosomes but is instead controlled by the polymerization state of the actin cytoskeleton. The results of this work show that the organization of the cytoskeleton is affected by processes specifically mediated or regulated by the mt1 receptor and may represent a novel alternative mechanism for the stimulation of process formation.

Actin Cytoskeleton↗
PubMed2000

Mapping the melatonin receptor. 6. Melatonin agonists and antagonists derived from 6H-isoindolo[2,1-a]indoles, 5,6-dihydroindolo[2,1-a]isoquinolines, and 6,7-dihydro-5H-benzo[c]azepino[2,1-a]indoles.

6H-Isoindolo[2,1-a]indoles (5, 7, 10, 13), 5,6-dihydroindolo[2, 1-a]isoquinolines (20, 21), and 6,7-dihydro-5H-benzo[c]azepino[2, 1-a]indoles (23, 25, 27, 30) have been prepared as melatonin analogues to investigate the nature of the binding site of the melatonin receptor. The affinity of analogues was determined in a radioligand binding assay using cloned human mt(1) and MT(2) receptor subtypes expressed in NIH 3T3 cells. Agonist and antagonist potency was measured using the pigment aggregation response of a clonal line of Xenopus laevis melanophores. The 2-methoxyisoindolo[2, 1-a]indoles (7a-d) showed much higher binding affinities than the parent isoindoles (5a-e), and whereas 7a-c were agonists in the functional assay, 7d and 5a-e were antagonists. The 2-ethoxyisoindolo[2,1-a]indoles (10a-d) showed reduced binding affinities compared to their methoxy analogues, while the 5-chloro derivative 13 showed a considerable reduction in binding affinity and potency compared to 7a. The 10-methoxy-5,6-dihydroindolo[2, 1-a]isoquinolines (21a-c) had higher binding affinities than the corresponding parent indoloisoquinolines (20a-c) in the human receptor subtypes, and the parent compounds were antagonists whereas the 10-methoxy derivatives were agonists in the functional assay. The N-cyclobutanecarbonyl derivatives of both the parent (20d) and 10-methoxyl (21d) series had similar binding affinities and were both antagonists with similar potencies. The 11-methoxy-6, 7-5H-benzo[c]azepino[2,1-a]indoles (25a-d) had higher binding affinities than the corresponding parent compounds (23a-d) at the MT(2) receptor but similar affinities at the mt(1) site; all of the compounds were antagonists in the functional assay. Changing 11-methoxy for 11-ethoxy decreased the binding affinity slightly, and this was more evident at the MT(2) receptor. All of the derivatives investigated had either the same or a greater affinity for the human MT(2) receptor compared to the mt(1) receptor (range 1:1-1:132). This suggests that the mt(1) and MT(2) receptor pockets differ in their ability to accommodate alkyl groups in the indole nitrogen region of the melatonin molecule. Two compounds (7c and 25c) were tested in functional assays on recombinant mt(1) and MT(2) melatonin receptors. Compound 7c is a potent agonist with some selectivity (44-fold) for the MT(2) receptor, while 25c is an MT(2)-preferring antagonist. Increasing the carbon chain length between N-1 of indole and the 2-phenyl group from n = 1 through n = 3 leads to a fairly regular decrease in the binding affinity, but, remarkably, when n = 3, it converts the methoxy compounds from melatonin agonists to antagonists. The Xenopus melatonin receptor thus cannot accommodate an N-n-alkyl chain attached to a 2-phenyl substituent with n > 2 in the required orientation to induce or stabilize the active receptor conformation.

3T3 Cells↗
PubMedDate not supplied

Guanosine 5'-O-(3-thiotriphosphate) and cations regulate melatonin receptors, and melatonin inhibits cyclic AMP production in the spinal cord.

Effects of guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S) and cations on 2-[125I]iodomelatonin binding were investigated in membrane preparations of the chicken spinal cord. At concentrations of 10 and 50 mumol/l, GTP gamma S dose-dependently increased (p < 0.05) the equilibrium dissociation constant (Kd) and depressed (p < 0.05) the maximum number of binding sites (Bmax). Na+ at a concentration of 125 mmol/l significantly increased (p < 0.05) the Kd and decreased (p < 0.05) the Bmax, and Mg2+ (2.5 mmol/l) significantly increased (p < 0.05) the Bmax without changes in Kd. In addition, Na+ and Mg2+ affected the interactions of GTP gamma S with melatonin receptors. In the spinal cord explants, melatonin (10 nmol/l) attenuated forskolin-stimulated cyclic AMP production by 53.1%, and preincubation with pertussis toxin abolished this effect of melatonin. These results suggest that the melatonin receptors in the chicken spinal cord are linked to its second messenger via a pertussis-toxin-sensitive guanine-nucleotide-binding protein, and that cations modulate these receptors. Our studies further support a previous hypothesis that melatonin exerts a direct action on spinal cord functions.

Animals↗
PubMed2003

Development of a high-throughput bioassay to screen melatonin receptor agonists using human melatonin receptor expressing CHO cells.

Melatonin receptors belong to the superfamily of G-protein-coupled receptors and appear to couple with Gi type of G protein, which has an inhibitory effect on the adenylate cyclase. Normally, melatonin dose not induce transient elevation of intracellular calcium concentration in CHO cells stably expressing melatonin receptors. Accordingly, the cells are unable to be used for fluorescent imaging plate reader (FLIPR), which is the device used to measure the cellular signal as a calcium elevation. To overcome this issue we tried to transfect chimeric G protein, Gqi5, into CHO cells expressing melatonin receptors. The Gqi5 is a chimeric Gq protein containing the five carboxyl-terminal amino acids from Gi, which interact with Gi-coupled receptor and possess the function of evaluating calcium concentration through the Gq pathway. The transfected cells result in a calcium elevation in a concentration-response manner. The specificity of this assay was similar to that of radioreceptor binding assay. Therefore, this FLIPR assay, using melatonin receptor and Gqi5 expressing CHO cells, is available for clinical bioassay of melatonin and for the screening of specific ligands of melatonin.

Animals↗
PubMed1998

Mapping the melatonin receptor. 5. Melatonin agonists and antagonists derived from tetrahydrocyclopent[b]indoles, tetrahydrocarbazoles and hexahydrocyclohept[b]indoles.

Tetrahydrocyclopent[b]indoles, tetrahydrocarbazoles, and hexahydrocyclohept[b]indoles have been prepared as melatonin analogues to investigate the nature of the binding site of the melatonin receptor. The affinity of analogues was compared in a radioligand binding assay using chicken brain membranes and agonist and antagonist potency measured in clonal Xenopus laevis melanophore cells. Comparison of the N-acyl-3-amino-6-methoxytetrahydrocarbazoles (2) with N-acyl-4-(aminomethyl)-6-methoxy-9-methyltetrahydrocarbazoles (9) showed that the latter have much higher binding affinities for the chicken brain receptor. Comparison of N-acyl-1-(aminomethyl)-7-methoxy-4-methyltetrahydrocyclopent[b]ind oles (10), 6-methoxytetrahydrocarbazoles (9), and N-acyl-10-(aminomethyl)-2-methoxy-5-methylhexahydrocyclohept[b]ind oles (11) showed that the tetrahydrocarbazoles had the highest binding affinity with the cyclohept[b]indoles and the cyclopent[b]indoles having rather lower affinities. All of these observations are in agreement with our postulated model of melatonin orientation at the binding pocket in which the 3-amidoethane side chain is in a conformation close to the 5-methoxyl group, as is shown in the X-ray crystallographic structure of 9m and in the energy-minimized computed structures. Separation of the enantiomers of members from each of these three systems was accomplished by chiral HPLC. It was found that in all cases the (-)-enantiomer had a higher binding affinity than the (+)-enantiomer. An X-ray crystallographic analysis of the two enantiomers of 9a showed that the (+)-enantiomer had the (R) absolute stereochemistry. Since the sign of the Cotton curves, determined from circular dichroism studies, was the same for all (+)-enantiomers, it is assumed that the absolute stereochemistry at these centers is identical. In the Xenopus melanophore assay, the tetrahydrocarbazoles 2 (R = H) were mainly weak antagonists, while those with R = OMe were agonists. The biological behavior of the tetrahydrocarbazoles 9 (R = H) depended on R1, some being agonists and some antagonists, whereas those with R = OMe were generally agonists. Variation of the R and R1 groups in compounds of type 9 produced both agonists and antagonists. The tetrahydrocylopentaindoles 10 had similar biological properties to the corresponding analogues of 9, but the hexahydrocycloheptaindoles 11 showed a much greater propensity to be antagonists. In all cases the (S)-enantiomers were found to be more potent agonists than the (R)-enantiomers.

Animals↗
PubMed1985

Characterization of a retinal melatonin receptor.

Melatonin (5-methoxy-N-acetyltryptamine) at picomolar concentrations (IC50, 40 pM) inhibited the calcium-dependent release of [3H]dopamine elicited at 3 Hz (2 min, 20 mA, 2 msec) from rabbit retina through activation of a site possessing the pharmacological and functional characteristics of a receptor. The effect of melatonin shows biological specificity as this hormone does not modify [3H]dopamine release from striatum or olfactory tubercle. This paper describes the effects of small modifications of the melatonin structure on the inhibition of calcium-dependent release of [3H]dopamine from retina. The more active melatonin analogs were those possessing a 5-methoxy group on carbon 5 of the indole nucleus and an N-acetyl group on the same position as in melatonin. The potencies of 5-methoxy indoles compounds was as follows (IC50): melatonin (40 pM) = 6-chloromelatonin (40 pM) greater than 6-hydroxymelatonin (1.6 nM) greater than or equal to 6-methoxymelatonin (2 nM) greater than 5-methoxytryptamine (63 nM) greater than 5-methoxy-N,N-di-methyltryptamine (200 nM) much greater than 5-methoxytryptophol (4 microM). The structure activity relationships of melatonin and related indoles indicated that the efficacy of melatonin is determined by the moiety substituted on carbon 5 (i.e., 5-methoxy group), whereas the affinity for the receptor is determined primarily by the moiety substituted on carbon 3 (i.e., ethyl N-acetyl group) of the indole nucleus. N-acetyltryptamine competitively antagonized the inhibitory effect of melatonin in the chicken retina and appears to be a partial agonist in the rabbit retina.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Daily rhythms of melatonin binding sites in the rat pars tuberalis and suprachiasmatic nuclei; evidence for a regulation of melatonin receptors by melatonin itself.

Using quantitative autoradiography, the density of melatonin binding sites has been measured in the rat pars tuberalis (PT) and suprachiasmatic nuclei (SCN) every 4 h throughout a 24-hour period in animals kept in a light regime of 12L/12D (with lights on at 07.00 h). Slices of PT and SCN were incubated in the presence of 180 and 172 pM, respectively, of 2-125I-melatonin. In both structures investigated, specific 2-125I-melatonin binding sites showed similar rhythms throughout the 24-hour period with a maximum at 16.00 h (PT: 46.9 +/- 2.8 fmol/mg protein, n = 5 and SCN: 5.12 +/- 0.30 fmol/mg protein, n = 5) and a minimum at 4.00 h (PT: 28.5 +/- 4.5 fmol/mg protein, n = 5 and SCN: 3.07 +/- 0.39 fmol/mg protein, n = 5). Similar experiments performed on PT of animals kept in constant light (LL) for 3 days revealed a lack of variations of melatonin binding site density, all the values being significantly higher than those of the respective 12L/12D group (concentration of 2-125I-melatonin used: 180 pM). All these preliminary results were confirmed by saturation studies performed at 16.00 and 4.00 h using quantitative autoradiography and in 12L/12D animals, using radioreceptor binding assays on isolated PT membranes. In 12L/12D animals, the maximum number of melatonin binding sites (Bmax) of both SCN and PT was significantly higher at 16.00 h than at 4.00 h. In all these cases, however, the dissociation constant (Kd) failed to show any significant daily variation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

An updated phylogenetic analysis of vertebrate melatonin receptor sequences: reflection on the melatonin receptor nomenclature by the Nomenclature Subcommittee of the International Union of Pharmacology.

In the past few years, significant progress on melatonin receptor research has led to the discovery of a family of genetically related but pharmacologically distinctive G-protein-coupled receptors in the vertebrates. With increasing number of receptor clones being identified, there is a need for a system of classification and nomenclature for these receptor subtypes. Recently, an updated nomenclature system, which has renamed the existing mammalian melatonin receptor clones, has been proposed by the relevant subcommittee of the International Union of Pharmacology (NC-IUPHAR). However, the majority of receptor clones which have been identified in non-mammalian vertebrates are not clearly defined by this system. By performing phylogenetic analysis of both mammalian and non-mammalian melatonin receptor clones, we would like to propose a classification-nomenclature system for vertebrate melatonin receptors. Hopefully, our system, which incorporates genetic data as well as the pharmacological criteria that have been adopted by the NC-IUPHAR nomenclature system, will provide the framework for future development of a unified scheme of classification and nomenclature for melatonin receptors.

Animals↗
PubMed2001

Chimeric Galphaq subunits can distinguish the long form of the Xenopus Mel1c melatonin receptor from the mammalian mt1 and MT2 melatonin receptors.

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 Galphaq 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 Galphaq chimeras, while the long form of Mel1c was totally ineffective. Among the Galphaq 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 Galphaq 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 Galphaq chimeras. The presence of the large C-terminal tail of Mel1c in Chi 1 and Chi 3 markedly hindered their coupling to the Galphaq chimeras. On the other hand, the attachment of either the mtl or MT2 C-terminal tail to a Mel1c backbone produced chimeras (Chi 2 and Chi 4) that were capable of activating the Galphaq chimeras. These findings suggest the involvement of C-terminal regions of melatonin receptors in the recognition of G proteins.

Animals↗
PubMed1996

Differential regulation of melatonin receptors in sheep, chicken and lizard brains by cholera and pertussis toxins and guanine nucleotides.

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.

Animals↗