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Research ArticleIUPHAR Nomenclature Reports

International Union of Basic and Clinical Pharmacology. LXXV. Nomenclature, Classification, and Pharmacology of G Protein-Coupled Melatonin Receptors

Margarita L. Dubocovich, Philippe Delagrange, Diana N. Krause, David Sugden, Daniel P. Cardinali and James Olcese
Pharmacological Reviews September 2010, 62 (3) 343-380; DOI: https://doi.org/10.1124/pr.110.002832

Article Figures & Data

Figures

  • Fig. 1.
    Fig. 1.

    Regulation of melatonin production and receptor function. Melatonin is synthesized in the pineal gland and in the retina. In the pineal gland, melatonin (MLT) synthesis follows a rhythm driven by the suprachiasmatic nucleus, the master biological clock. Neural signals from the SCN follow a multisynaptic pathway to the superior cervical ganglia. Norepinephrine released from postganglionic fibers activates α1- and β1-adrenoceptors in the pinealocyte, leading to increases in second messengers (i.e., cAMP and inositol trisphosphate) and the activity of AA-NAT, the rate-limiting step in melatonin synthesis. The system is dramatically inhibited by light, the external cue that allows entrainment to the environmental light/dark cycle. The photic signal received by the retina is transmitted to the SCN via the retinohypothalamic tract, which originates in a subset of retinal ganglion cells. Pineal melatonin thus serves as the internal signal that relays day length, allowing regulation of neuronal activity (MT1) and circadian rhythms (MT1, MT2) in the SCN (Dubocovich, 2007), of neurochemical function in brain through the MT1 and MT2 receptors (Dubocovich, 2006), of vascular tone through activation of MT1 (constriction) and MT2 receptors (dilation) in arterial beds (Masana et al., 2002), and seasonal changes in reproductive physiology and behavior through activation of MT1 receptors in the pars tuberalis (Duncan, 2007). The pars tuberalis of the pituitary gland interprets this rhythmic melatonin signal and generates a precise cycle of expression of circadian genes through activation of MT1 receptors. Melatonin synthesis in the photoreceptors of the retina follows a similar circadian rhythm generated by local oscillators (Tosini et al., 2007). Activation of MT1 and MT2 melatonin receptors regulate retina function and hence transmission of photic information to the brain (Dubocovich et al., 1997). [Adapted from Dubocovich ML and Masana M (2003) Melatonin receptor signaling, in Encyclopedia of Hormones and Related Cell Regulators (Henry H and Norman A eds), pp 638–644, Academic Press, San Diego, CA. Copyright © 2003 Academic Press. Used with permission.]

  • Fig. 2.
    Fig. 2.

    Melatonin synthesis. Melatonin (MLT) is synthesized from serotonin through two enzymatic steps. First, serotonin is acetylated by NAT to yield N-acetylserotonin (NAS). The second step involves transfer of a methyl group from (S)-adenosylmethionine to the 5-hydroxyl group of N-acetylserotonin via the enzyme HIOMT. The rhythms of melatonin and serotonin have opposite phase during subjective night and day (Klein, 1999).

  • Fig. 3.
    Fig. 3.

    Membrane topology of the hMT1 melatonin receptor showing amino acids conserved in the hMT2 receptor. Gray circles denote amino acids identical in the hMT1 and hMT2 melatonin receptors. The two glycosylation sites on the hMT1 receptor are denoted (Y) in the N terminus. [Adapted from Reppert SM and Weaver DR (1995) Melatonin madness. Cell 83:1059–1062. Copyright © 1995 Elsevier Inc. Used with permission.]

  • Fig. 4.
    Fig. 4.

    MT1 and MT2 melatonin receptor dendrogram. Phylogenetic tree of melatonin receptor or melatonin receptor-related (GPR50, melatonin-related receptor or H9) sequences. The evolutionary distances between the different sequences were calculated with the matrix of Blosum 62 score. The tree was drawn using the Unweighted Pair Group Method with Arithmetic mean (UPGMA). GenBank accession numbers and the number of amino acids for each receptor are as follows: human H9: U52219, 613; sheep H9: U52221, 613; mouse H9: AF065145, 791; cattle MT1: U73327, 257; sheep MT1: U14109, 366; Djungarian hamster MT1: U14110, 353; golden hamster MT1: AF061158, 325; mouse MT1: U52222, 353; rat MT1: AF130341, 326; human MT1: U14108, 350; Pig MT1: U73326, 154; mouse MT2: AY145850, 365; rat MT2: U28218, 120; human MT2: U25341, 362. The sequences for cattle and pig MT1 receptors have been partially cloned.

  • Fig. 5.
    Fig. 5.

    MT1 and MT2 melatonin receptor 3 dimensional models and putative mode of binding for melatonin. A and B show critical amino acids residues for melatonin binding to the MT1 and MT2 melatonin receptors, respectively. The amino acids labeled in white have been defined by site-directed mutagenesis to modulate binding affinity (see Table 2 and 3). C and D show interactions among melatonin and key amino acid residues important for binding to the MT1 and MT2 melatonin receptors, respectively. [Adapted from Farce A, Chugunov AO, Logé C, Sabaouni A, Yous S, Dilly S, Renault N, Vergoten G, Efremov RG, Lesieur D, and Chavatte P (2008) Homology modelling of MT1 and MT2 receptors. Eur J Med Chem 43:1926–1944. Copyright © 2008 Elsevier Masson SAS. Used with permission.]

  • Fig. 6.
    Fig. 6.

    MT1 and MT2 melatonin receptor signaling. A, melatonin (MLT) signals through activation of the MT1 receptor via two parallel pathways mediated by the α-subunit (i.e., inhibition of cAMP formation) and the βγ-subunits [i.e., potentiation of phosphoinositide turnover stimulated by a Gq-coupled receptor (R)] of Gi. B, signaling pathways coupled to MT2 melatonin receptor activation. Melatonin-mediated phase shifts of circadian rhythms through MT2 receptors are mediated by PKC activation (the mechanism leading to PKC activation remains putative, however). DAG, diacylglycerol; PKA, protein kinase A; R, Gq-coupled receptor (i.e., prostaglandin F2α receptor FP and purinergic receptor P2Y) (Masana and Dubocovich, 2001). [Adapted from Masana MI and Dubocovich ML (2001) Melatonin receptor signaling: finding the path through the dark. Sci STKE 2001:pe39. Copyright © 2001 American Association for the Advancement of Science. Used with permission.]

  • Fig. 7.

    Chemical structure of melatonin receptor ligands. A, chemical structures of nonselective MT1/MT2 ligands. B, chemical structures of selective MT1 melatonin receptor ligands. C, chemical structures of selective MT2 melatonin receptor ligands. Chemical names (see also the abbreviations list at the bottom of the first page of the article): compound 11, 1-(cyclopropylcarbonyl)-4-[(1R)-6-methoxy-2,3-hidro-1H-inden-1-yl]piperazine; compound 12, N-[(1-p-chlorobenzyl-4-methoxy-1H-indol-2-yl)methyl]propanamide; compound 13, (R)-4-(2.3-dihydro-6-methoxy-1H-inden-1-yl)-N-ethyl-1-piperazine carboxamide; DH 97, N-pentanoyl-2-benzyltryptamine; GR 128107, 3-(1-acetyl-3-piperidinyl)-5-methoxyindole; GR 135533, 3-(N-ethyl-2-pyrrolidinone)5-methoxyindole; GR 196429, N-(2-[2,3,7,8-tetrahydro-1H-furo{2,3-g}indol-1-yl]ethyl)acetamide; IIK7, N-butanoyl-2-(2-methoxy-6H-isoindolo [2,1-a]indol-11-yl)ethanamine; K185, N-butanoyl-2-(5,6,7-trihydro-11-methoxybenzo[3,4]cyclohept[2,1-a]indol-13-yl) ethanamine; luzindole, 2-benzyl-N-acetyltryptamine; LY 156735, N-[2-(6-chloro-5-methoxy-1H-indol-3-yl)propyl]acetamide; N 0889, 2-benzyl-N-propionyl-acetyltryptamine; N 0891, 2-(p-methyl-benzyl)-N-acetyltryptamine; S 20098, N-(2-[7-methoxy-1-naphthalenyl]ethyl)acetamide; S 20928, N-[2-naphth-1-yl-ethyl]-cyclobutyl carboxamide; S 22153, N-[2-(5-ethylbenzo[b]thiophen-3-yl)ethyl]acetamide; S 24014, N-[2-(2-(3-methoxybenzyl)5-methoxy benzo(b)furan-3-yl)ethyl]acetamide; S 24635, N-[2-(5-carbamoylbenzofuran-3-yl)ethyl]acetamide; S 24773, N-{2-[3-(3-aminophenyl)-7-methoxy-1-naphthyl]ethyl}acetamide; S 25726, N-methyl-(3-{2-[(cyclopropylcarbonyl)amino]ethyl}benzo[b]furan-5-yl)carbamate; S 25567, (R,S)-N-[2-(6-hexyloxy-3,4 dihydro-2H-1-benzopyran-4-yl)ethyl]acetamide; S 26131, N-(2-{7-[3-({8-[2-acetylamino) ethyl]-2-naphtyl}oxy)propoxy]-1-naphthyl}ethyl)acetamide; S 26284, N-(2-{7-[4-({8-[2-acetylamino)ethyl]-2-naphtyl}oxy)butoxy]-1-naphthyl}ethyl)acetamide; S 26553, N-methyl-1{1-[2-(acetylamino)ethyl]naphthalen-7-yl}carbamate; S 27533, N-[2-(5-methoxy-1-methyl-4-nitroindol-3-yl)ethyl]acetamide; S 28407, N-[2-(7-methoxy-3-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)ethyl]cyclobutyl carboxamide; TAK-375, (S)-N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)-ethyl]propionamide.

Tables

  • TABLE 1

    IUPHAR melatonin receptor nomenclature and classification

    NomenclatureMT1MT2MT3
    Previous namesMEL1A, ML1A, Mel1aMEL1B, ML1B, Mel1bML2
    Structural information7TM7TM
    Gene/chromosome
        Human350 aa,a P48039; chr 4q 35.1362 aa,b P49286; chr 11q21–22
        Mouse353 aa,c Q61184; chr 8365 aa,d U57554; chr 9
    Selective agonistsS 26284eIIK7 (10.3)fN-Acetylserotonin,g–k 5MCA-NATk
    Selective antagonistsS 26131e4P-ADOT,l,m 4P-PDOT (8.8),l,m GR 128107l, K185 (9.3)fPrazosinh
    Radioligands[3H]MLT,n 2- [125I]IMLTo[3H]MLT,n 2-[125I]IMLT,o [3H]4P-PDOTp2-[125I]5MCA-NAT,k 2-[125I]IMLTn
    Tissue FunctionsVascular vasoconstriction,q–u inhibition neuronal firing,v phase-shift circadian activity rhythmsuVascular vasodilation,t inhibition retinal dopamine release,l phase-shift circadian rhythms of neuronal firingm,w,v,xLeukocyte adhesionu
    CommentsMT1 full-length cDNAs were cloned from human (350 aa),a mouse (353 aa),c sheep (366 aa),a rat (353 aa),y hamster (353 aa),z monkey (352),aa and partial cDNAs from cattle (257 aa) and pig (154 aa).bbMT2 cDNA was cloned from human (362 aa),z rat (364 aa),y mouse (365 aa),d sheep (376 aa),cc monkey (362 aa),aa and partial cDNA from hamster.zEndogenous ligands are MLT and N-acetylserotonin. A recent report identifies an MT3 binding site in hamster kidney as the enzyme quinone reductase-2.dd Antagonist potencies have not yet been established.

    • aa, amino acid(s); chr, chromosome; 5MCA-NAT, 5-methoxycarbonylamino-N-acetyltryptamine.

    • ↵a Reppert et al., 1994.

    • ↵b Reppert et al., 1995a.

    • ↵c Roca et al., 1996.

    • ↵d Jin et al., 2003.

    • ↵e Audinot et al., 2003.

    • ↵f Faust et al., 2000.

    • ↵g Dubocovich, 1988b.

    • ↵h Lucchelli et al., 1997.

    • ↵i Eison and Mullins, 1993.

    • ↵j Popova and Dubocovich, 1995.

    • ↵k Molinari et al., 1996.

    • ↵l Dubocovich et al., 1997.

    • ↵m Dubocovich et al., 1998b.

    • ↵n Browning et al., 2000.

    • ↵o Dubocovich and Takahashi, 1987.

    • ↵p Dubocovich and Masana, 1999.

    • ↵q Ting et al., 1999.

    • ↵r Ting et al., 1997.

    • ↵s Masana et al., 2002.

    • ↵t Doolen et al., 1998.

    • ↵u Lotufo et al., 2001.

    • ↵v Liu et al., 1997.

    • ↵w Dubocovich et al., 2005.

    • ↵x Hunt et al., 2001.

    • ↵y Audinot et al., 2008.

    • ↵z Weaver et al., 1996.

    • ↵aa Nishiyama et al., 2009.

    • ↵bb Messer et al., 1997.

    • ↵cc Cogé et al, 2009.

    • ↵dd Nosjean et al., 2000.

  • TABLE 2

    Effect of amino acid mutations on ligand binding to the MT1 melatonin receptor

    Amino acids are represented in single-letter code with position number shown. Superscripts after the second amino acid indicate that the substituted amino acid represents the amino acid in the designated receptor at the analogous position. The position in the transmembrane domain is indicated using the numbering scheme of Ballesteros and Weinstein (1995).

    Amino Acid Mutation SchemeTM No.SpeciesExpression SystemCharacterizationReference
    R54W(1.59)HumanCOS cellsHeterozygous polymorphism with no phenotype. Decreased Bmax (3.5×) and slightly increased Kd.Ebisawa et al., 1999
    S103A(2.28)HumanCOS-7No change in Bmax or Kd.Conway et al., 2001
    M107T(3.32)HumanCOS-7No change in Bmax or Kd.Conway et al., 2001; Kokkola et al., 1998
    S110Aa(3.35)HumanCOS-7Decreased Bmax (10×), increased Kd (8×) and EC50 of cAMP production (22×). No change in Ki of luzindoleConway et al., 2001
    S114Aa(3.39)HumanCOS-7Decreased Bmax (4×), increased Kd (9×) and EC50 of cAMP production (14×). No change in Ki of luzindole.Conway et al., 2001
    N124A/K(3.49)HumanAtT20Decreased Bmax (21×), tends to be retained in Golgi. No specific binding.Nelson et al., 2001
    N124A(3.49)HumanSaccharomyces cerevisiaeIncreased EC50 for melatonin (230×).Kokkola et al., 1998
    N124L(3.49)HumanAtT20Decreased Bmax (21×), tends to be aggregated near surface. No specific binding.Nelson et al., 2001
    N124D/E(3.49)HumanAtT20No change in Bmax or Kd. Melatonin induced inhibition of cAMP (efficacy) and voltage-sensitive Ca2+ channels, but not Kir3.1/3.2 potassium channel activation.Nelson et al., 2001
    A157V(4.55)HumanCOS cellsHeterozygous polymorphism with no phenotype. No change in Bmax or Kd.Ebisawa et al., 1999
    H195Aa(5.46)HumanS. cerevisiaeDecreased EC50 (3–6×). N-acetylserotonin gave an apparent saturable response, whereas the wild-type receptor did not saturate at the same concentrations.Kokkola et al., 1998
    H211F/l(5.46)OvineCOS-7Increase Kd (6×) with melatonin. Decreased Ki (3–15×) with N-NEA. No change in Ki with N-acetylserotonin.Conway et al., 1997
    V192T + H195A(5.42 + 5.46)HumanS. cerevisiaeNo specific responseKokkola et al., 1998
    V208A(5.42)OvineCOS-7No change in Kd or in Ki of several melatonin analogs.Conway et al., 1997
    V208L(5.42)OvineCOS-7Increased Kd and Ki for several melatonin analogs (5–12×).Conway et al., 1997
    A252C(6.49)HumanCOS-7No change in Kd or Bmax.Conway et al., 2000
    HumanCOS-7No change in Kd or Bmax.Gubitz and Reppert, 2000
    G258T(6.55)HumanCOS-7Specific binding drastically reducedGubitz and Reppert, 2000; Conway et al., 2000
    A252C + G258T(6.49 + 6.55)HumanCOS-7No specific bindingGubitz and Reppert, 2000
    P253A(6.50)HumanS. cerevisiaeNo specific response.Kokkola et al., 1998
    A202D, H342R, I347V(ext. loop3, C-terminal)OvineL-cellsPolymorphism of previously cloned ovine MT1. No phenotype in vivo and fully functional in mouse. L cells as shown by high affinity binding, competition binding analysis, GTPγS and inhibition of cAMP.Barrett et al., 1997
    S280A(7.38)HumanS. cerevisiaeNo change in apparent EC50Kokkola et al., 1998
    S280F + A284G(7.38 + 7.42)HumanS. cerevisiaeNo specific responseKokkola et al., 1998

    • N-NEA, N-[2-(1-naphthyl) ethyl]acetamide.

    • ↵a Amino acid residues important for modulating binding to the MT1 receptor (Farce et al., 2008).

  • TABLE 3

    Effect of amino acid mutations on ligand binding to the hMT2 melatonin receptor

    Amino acids are represented in single-letter code with position number shown. Superscripts after the second amino acid indicate that the substituted amino acid represents the amino acid in the designated receptor at the analogous position. The position in the transmembrane domain is indicated using the numbering scheme of Ballesteros and Weinstein (1995).

    Amino Acid Mutation SchemeTM No.Expression SystemCharacterizationReference
    Human
        G24ENTermCOS-7Heterozygous polymorphism with no phenotype. When expressed in COS-7 cells no change in Kd or Ki with melatonin.Ebisawa et al., 2000
        L66F1.58COS-7Heterozygous polymorphism with no phenotype.Ebisawa et al., 2000
        C113AECL1HEK293No specific binding.Mseeh et al., 2002
        C140AICL2HEK293No change in Kd, slightly increased Ki for melatonin (1.6×), decreased Bmax (22×).Mseeh et al., 2002
        C143AICL2HEK293No change in Kd, slightly increased Ki for melatonin (1.4×), slightly increased Bmax (1.8×).Mseeh et al., 2002
        C190AECL2HEK293No specific binding.Mseeh et al., 2002
        C219A5.57HEK293No change in Kd or Ki. Decreased Bmax (5×).Mseeh et al., 2002
        C263A6.47HEK293No change in Kd or Ki. Decreased Bmax (31×).Mseeh et al., 2002
        C302A7.47HEK293No change in Kd or Ki. Decreased Bmax (4×).Mseeh et al., 2002
        S123A3.35HEK293No change in Kd or Ki. Decreased Bmax (5×).Gerdin et al., 2003
        S127A3.39HEK293No change in Kd or Ki. Decreased Bmax (3×).Gerdin et al., 2003
        N175Aa4.60HEK293No change in Kd, slightly increased Ki for melatonin. No change in Bmax.Gerdin et al., 2003
        H208Aa5.46HEK293Increased Kd and Ki for melatonin. No change in Bmax.Gerdin et al., 2003
        F257A6.41HEK293No change in Kd or Ki. No change in Bmax.Gerdin et al., 2003
        W264A6.48HEK293Decreased Kd, no change in Ki. Decreased Bmax (22×).Gerdin et al., 2003
        S293A7.38HEK293No change in Kd or Ki. No change in Bmax.Gerdin et al., 2003
        V204Aa5.42HEK293No specific binding.Mazna et al., 2004
        V2055.43HEK293No change in Kd. No change in Bmax.Mazna et al., 2004
        F209A5.47HEK293No change in Kd. Decreased Bmax. No change in Ki for melatonin, luzindole or 4P-PDOT.Mazna et al., 2004
        G271T6.55HEK293Not saturable.Mazna et al., 2004
        L272Aa6.56HEK293No specific binding.Mazna et al., 2004
        Y298Aa7.43HEK293No specific binding.Mazna et al., 2004
        M120A3.32HEK293No change in Kd or Bmax.Mazna et al., 2005
        G121A3.33HEK293No change in Kd or Bmax.Mazna et al., 2005
        G121I3.33HEK293No change in Kd or Bmax.Mazna et al., 2005
        V124A3.36HEK293No change in Kd with decreased Bmax.Mazna et al., 2005
        I125A3.37HEK293No change in Kd or Bmax.Mazna et al., 2005
        Y188AECL2HEK293No specific binding.Mazna et al., 2005
        Y188FECL2HEK293No specific binding.Mazna et al., 2005
        N268Aa6.52HEK293No specific binding.Mazna et al., 2005
        N268Da6.52HEK293No specific binding.Mazna et al., 2005
        N268La6.52HEK293No specific binding.Mazna et al., 2005
        N268Qa6.52HEK293No change in Kd or Bmax.Mazna et al., 2005
        A275I6.59HEK293No specific binding.Mazna et al., 2005
        A275Va6.59HEK293No change in Kd or Bmax.Mazna et al., 2005
        V291Aa7.36HEK293No specific binding.Mazna et al., 2005
        V291Ia7.36HEK293No specific binding.Mazna et al., 2005
        L295Aa7.40HEK293No specific binding.Mazna et al., 2005
        L295Ia7.40HEK293No specific binding.Mazna et al., 2005
        L295Va7.40HEK293No specific binding.Mazna et al., 2005
    Hamster
        P41A1.33CHO-K1No change in Kd or Bmax. No change in EC50 or Emax for melatonin or 2-iodomelatonin stimulation of GTPγ35S binding.Mazna et al., 2008
        P93A2.57CHO-K1No change in Kd or Bmax. No change in EC50 or Emax for melatonin or 2-iodomelatonin stimulation of GTPγ35S binding.Mazna et al., 2008
        P95A2.59CHO-K1No change in Kd or Bmax. No change in EC50 or Emax for melatonin or 2-iodomelatonin stimulation of GTPγ35S binding.Mazna et al., 2008
        P158A4.40CHO-K1No change in Kd or Bmax. No change in EC50 or Emax for melatonin or 2-iodomelatonin stimulation of GTPγ35S binding.Mazna et al., 2008
        P174A4.59CHO-K1No specific binding.Mazna et al., 2008
        P174G4.59CHO-K1No specific binding.Mazna et al., 2008
        P212A5.50CHO-K1No change in Kd or Bmax. Decreased Emax for melatonin and 2-iodomelatonin, stimulation of GTPγ35S binding.Mazna et al., 2008
        P212G5.50CHO-K1No change in Kd or Bmax. Increased EC50 for 2-iodomelatonin stimulation of GTPγ35S binding with no change in Emax.Mazna et al., 2008
        P266A6.50CHO-K1No specific binding.Mazna et al., 2008
        P266G6.50CHO-K1No specific binding.Mazna et al., 2008
        A305P7.50CHO-K1No specific binding.Mazna et al., 2008
        A305V7.50CHO-K1No change for Kd or Bmax. Increased EC50 for melatonin and 2-iodomelatonin stimulation of GTPγ35S binding with decreased Emax.Mazna et al., 2008

    • HEK, human embryonic kidney; CHO, Chinese hamster ovary.

    • ↵a Amino acid residues important for modulating binding to the MT1 receptor (Farce et al., 2008).

  • TABLE 4

    Pharmacological profile of ligands with agonist/partial agonist efficacy on hMT1, hMT2 and native melatonin receptors

    pKi, pEC50, and pIC50 values were obtained as detailed in footnotes.

    2-[125I]IMLT Binding (COS-7 Cells)aCHO CellsInhibition [3H]Dopamine Release in Rabbit Retinad (pIC50)
    Stimulation GTPγS BindingbInhibition-Forskolin Stimulated cAMP Accumulationc
    hMT1 (pKi)hMT2(pKi)Ki Ratio (MT1/MT2)hMT1 (pEC50)hMT2 (pEC50)pEC50 Ratio (MT1/MT2)hMT1 (pEC50)hMT2 (pEC50)pEC50 Ratio (MT1/MT2)
    2-Iodomelatonin10.29.70.39.79.81.11110.10.111.2
    S 200989.110.2148.810169.410.37.912
    Melatonin9.19.84.98.69.84.59.59.71.610.7
    GR1964298.6e9.3e4.7e89.012.610.5
    6-Chloromelatonin7.99.7578.39.39.68.19.85010.4
    6-Hydroxymelatonin9.48.37.37.27.40.68.7
    5-Methoxyluzindole7.59.6130N.D.N.D.1.3
    8M-PDOT7.28.520N.D.N.D.9.3
    N-Acetylserotonin6.76.71.25.76.67.97.3
    5-MCA-NAT5.66.610N.D.N.D.N.D.
    IIK78.4f10.3f908.7f10.3f44N.D.

    • IMLT, iodomelatonin; N.D., not determined.

    • ↵a Dubocovich et al. (1997); COS-7 cells transiently transfected.

    • ↵b Audinot et al. (2003).

    • ↵c Browning et al., (2000); CHO cells stably transfected.

    • ↵d Dubocovich (1985, 1995); inhibition of calcium dependent release of dopamine elicited by electrical stimulation.

    • ↵e M. L. Dubocovich, unpublished observations; CHO cells stably transfected.

    • ↵f Faust et al. (2000); NIH 3T3 cells stably transfected.

  • TABLE 5

    Pharmacological profile of partial agonists/antagonists on hMT1, hMT2, and native melatonin receptors

    All values are from Dubocovich et al. (1997) except as noted otherwise.

    Melatonin Receptor Ligands2-[125]IMLT Binding[3H]DA Release in Rabbit Retina MT2 (pA2)GTPγS Binding
    Ratio hMT1/ hMT2hMT1 pKihMT2 pKihMT1KBhMT2KBRatio hMT1/ hMT2
    4P-CADOT3626.59.19.3
    4P-ADOT3306.28.98.8
    4P-PDOT3116.38.89.5
    K185a1327.29.3N.D.
    5-Methoxyluzindole1307.59.610.2
    S 24014b1257.59.67.38.830
    GR 1281071137.09.110.2
    N 0891916.18.07.7
    DH97c896.18.0N.D.
    N 0890566.27.97.5
    N 0889316.88.37.8
    Luzindole166.88.07.7
    N-Acetyltryptamine156.77.98.0
    GR 135533156.57.78.6
    S 20928b3.17.958.227.17.97.1
    S 22153b1.98.858.158.57.92.5
    5-HEATd0.27.87.1N.D.
    S 25567b0.168.57.78.47.70.23
    S 26284b0.018.85787.40.28
    S 26131b0.018.856.98.36.80.04

    • IMLT, iodomelatonin; DA, dopamine; 4P-CADOT, 4-phenyl-2-chloro-acetamidotetraline; N.D., not determined; 5-HEAT, 5-hydroxyethoxy-N-acetyltryptamine.

    • ↵a Values from Faust et al., 2000.

    • ↵b Audinot et al., 2003.

    • ↵c Teh and Sugden, 1999.

    • ↵d Nonno et al., 2000.

  • TABLE 6

    Melatonin receptor-mediated functional responses in native tissues

    Modified from Dubocovich et al. (2003).

    FunctionReceptorSignalingTissueApproachReferences
    CNS
        Inhibition—neuronal firing in the SCNMT1Increase in K+ conductance?SCNMT1-KOLiu et al., 1997; Jin et al., 2003
        Inhibition—PACAP-stimulated CREB phosphorylationMT1cAMP InhibitionSCNMT1-KOvon Gall et al., 2000
    MT1MT2-KOJin et al., 2003
        Phase shift—circadian rhythm of neuronal firing rhythms in the SCN brain sliceMT1UNKSCNMT1-KOLiu et al., 1997; Dubocovich et al., 2005
    MT2PKC activation4P-PDOTHunt et al., 2001
        Phase shift—circadian rhythm of wheel activityMT1UNKMT1-KODubocovich et al., 2005
    MT2-KO
    MT1MT2-KO
        Inhibition—dopamine release from rabbit retinaMT2UNKRabbit retinaCorrelation between antagonist KB in retina and Ki values on MT2 recombinant receptorsDubocovich et al., 1997
        Inhibition—long term potentiationMT2cAMP/PKA InhibitionHippocampus4P-PDOTWang et al., 2005
    MT2-KO
    Luzindole
    4P-PDOT
    Hypothalamic-Hypophyseal-Gonadal Axis
        Inhibition—prolactin secretionMT1UNKAnterior pituitaryMT1-KOvon Gall et al., 2002a
        Regulation of Per1 gene expressionMT1cAMP InhibitionAnterior pituitaryMT1-KOvon Gall et al., 2002a
        Inhibition—Testosterone secretionMT1cAMP inhibitionLeydig cells in testisLuzindoleFrungieri et al., 2005
    MT1 antibody
        Inhibition—Cortisol secretionMT1Corticotropin/CRH inhibitionAdrenal from Capuchin monkeyLuzindoleTorres-Farfan et al., 2003, 2004
        Regulation of oxytocin receptor gene expression and contractility in uterusMT2PLC, PKC activationHuman myometrium4P-PDOTSharkey and Olcese, 2007; Sharkey et al. 2009
        Regulation of photoperiodic informationMT1Type 2 and 3 deiodinasePars tuberalisMT1-KOYasuo et al., 2009
    MT2-KO
    MT1MT2-KO
    Cardiovascular
        VasoconstrictionMT1Activation of BKCa channelRat caudal arteryLuzindoleKrause et al., 1995; Geary et al., 1997, 1998; Viswanathan et al., 1997; Ting et al., 1999
    Cerebral arteries
        VasodilationMT2UNKRat caudal artery4P-ADOTDoolen et al., 1998; Masana et al., 2002
    4P-PDOT
    Immune
        Increase—splenocyte proliferation (i.e., cell-mediated immunity)MT2UNKSpleenMT1-KODrazen and Nelson, 2001
        Increase—serum anti-keyhole IgG concentrations (i.e., humoral immunity)MT2UNKT cellsMT1-KODrazen and Nelson, 2001
        Inhibition of leukocyte rollingMT2UNKMicrovasculature4P-PDOTLotufo et al., 2001
    Metabolism
        Inhibition—insulin secretionMT1cAMP inhibitionPancreatic β-cells4P-PDOTPeschke et al., 2000, 2002; Kemp et al., 2002; Mühlbauer et al., 2009
    GLP-1 inhibitionLuzindole
    MT1-KO
    MT2-KO
    MT1MT2-KO
        Inhibition—insulin secretionMT2cAMP InhibitionPancreatic β-cellsMT1-KOMühlbauer et al., 2009
    MT2-KO
    MT1MT2-KO
        Increased leptin productionMT1cAMPEpididymal adipocytes4P-PDOTAlonso-Vale et al., 2005
    Luzindole
    Cancer
        Inhibition—cancer cell proliferationMT1cAMPBreast tumor4P-PDOTDauchy et al., 2003; Blask et al., 2005a,b
    Linoleic acid uptakeRat hepatomaLuzindole
    13-HODE productionS20928
        Inhibition—cell proliferationMT2cAMPJAr cellsLuzindoleShiu et al., 1999; Dauchy et al., 2003
    Linoleic acid uptakeRat hepatoma4P-PDOT
    13-HODE production

    • UNK, unknown/undetermined etiology; PKA, protein kinase A; CRH, corticotropin-releasing hormone; PLC, phospholipase C; GLP-1, glucagon-like peptide; 13-HODE, (±)-13-hydroxy-9Z,11E-octadecadienoic acid.

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Research ArticleIUPHAR Nomenclature Reports

International Union of Basic and Clinical Pharmacology. LXXV. Nomenclature, Classification, and Pharmacology of G Protein-Coupled Melatonin Receptors

Margarita L. Dubocovich, Philippe Delagrange, Diana N. Krause, David Sugden, Daniel P. Cardinali and James Olcese
Pharmacological Reviews September 1, 2010, 62 (3) 343-380; DOI: https://doi.org/10.1124/pr.110.002832
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