Melatonin

Overview: Melatonin receptors (nomenclature as agreed by NC-IUPHAR Subcommittee on melatonin receptors, see Dubocovich et al., 1998; 2000) are activated by the endogenous ligands melatonin and N-acetylserotonin.

Nomenclature	MT1	MT2
Other names	MEL1A, ML1A, Mel1a	MEL1B, ML1B, Mel1b
Ensembl ID	ENSG00000168412	ENSG00000134640
Principal transduction	Gi/o	Gi/o
Selective agonists	–	IIK7 (Sugden et al., 1999), 5-methoxyluzindole (Dubocovich et al., 1998)
Selective antagonists	–	K185 (9.3, Sugden et al., 1999), 4P-PDOT (8.8, Dubocovich et al., 1997; Dubocovich et al., 1998), DH97 (8.0, Teh and Sugden, 1998)
Probes	[3H]-melatonin (Browning et al., 2000)	[3H]-melatonin (Browning et al., 2000)

Melatonin, 2-iodo-melatonin, S20098, GR196429, LY156735 and TAK375 (Kato et al., 2005) are non-selective agonists for MT₁ and MT₂ receptors. 2-Iodo-[¹²⁵I]-melatonin can be used to label all three melatonin receptor subtypes. (-)-AMMTC displays an ∼400-fold greater agonist potency than (+)-AMMTC at rat MT₁ receptors (Ting et al., 1999). Luzindole is a non-selective melatonin receptor antagonist with some selectivity for the MT₂ receptor (Dubocovich et al., 1998). MT₁/MT₂ heterodimers present different pharmacological profiles from MT₁ and MT₂ receptors (Ayoub et al., 2004).

The MT₃ binding site of hamster kidney, also termed the Mel₂ receptor, which binds 2-iodo-[¹²⁵I]-5MCA-NAT (Molinari et al., 1996), was identified as the hamster homologue of human quinone reductase 2 (ENSG00000124588, Nosjean et al., 2000; Nosjean et al., 2001). Pharmacological investigations of MT₃ binding sites have primarily been conducted in hamster and guinea-pig tissues. At this site, N-acetylserotonin (Eison and Mullins, 1993; Popova and Dubocovich, 1995; Molinari et al., 1996; Lucchelli et al., 1997) and 5MCA-NAT (Popova and Dubocovich, 1995) appear to function as agonists, while prazosin (Lucchelli et al., 1997) functions as an antagonist. A suggested physiological function of the MT₃ receptor is in the control of intraocular pressure in rabbits (Pintor et al., 2003). Xenopus melanophores and chick brain express a distinct receptor (x420, P49219; c346, P49288, initially termed Mel_1C) coupled to the G_i/o family of G proteins, for which GPR50 has recently been suggested to be a mammalian counterpart (see Dufourny et al., 2008).

Glossary

Abbreviations:

4P-PDOT

4-phenyl-2-propionamidotetraline

5MCA-NAT

5-methoxy-carbonylamino-N-acetyltryptamine

AMMTC

N-acetyl-4-aminomethyl-6-methoxy-9-methyl-1,2,3,4-tetrahydrocarbazole

DH97

2-benzyl-N-pentanoyltryptamine

GR196429

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

LY156735

β-methyl-6-chloromelatonin

S20098

N-(2-[7-methoxy-1-naphthalenyl]ethyl)acetamide

TAK375

(S)-N-[2(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide

Further Reading

Alarma-Estrany P, Pintor J (2007). Melatonin receptors in the eye: location, second messengers and role in ocular physiology. Pharmacol Ther113: 507–522.

Ambriz-Tututi M, Rocha-Gonzalez HI, Cruz SL, Granados-Soto V (2009). Melatonin: a hormone that modulates pain. Life Sci84: 489–498.

Dubocovich ML, Cardinali DP, Guardiola-Lemaitre B, Hagan RM, Krause DN, Sugden D, et al. (1998). Melatonin receptors. In: Girdlestone D (ed.). The IUPHAR Compendium of Receptor Characterization and Classification. IUPHAR Media: London, pp. 187–193.

Dubocovich ML, Cardinali DP, Delagrange PRM, Krause DN, Strosberg D, Sugden D, et al. (2000). Melatonin Receptors. In: Girdlestone D (ed.). The IUPHAR Compendium of Receptor Characterization and Classification, 2nd edn. IUPHAR Media: London, pp. 270–277.

Dubocovich ML, Rivera-Bermudez MA, Gerdin MJ, Masana MI (2003). Molecular pharmacology, regulation and function of mammalian melatonin receptors. Frontiers in Bioscience8: d1093–d1108.

Dufourny L, Levasseur A, Migaud M, Callebaut I, Pontarotti P, Malpaux B et al. (2008). GPR50 is the mammalian ortholog of Mel1c: evidence of rapid evolution in mammals. BMC Evol Biol8: 105.

Falcon J, Besseau L, Sauzet S, Boeuf G (2007). Melatonin effects on the hypothalamo-pituitary axis in fish. Trends Endocrinol Metab18: 81–88.

Hardeland R (2008). Melatonin, hormone of darkness and more: occurrence, control mechanisms, actions and bioactive metabolites. Cell Mol Life Sci65: 2001–2018.

Jockers R, Maurice P, Boutin JA, Delagrange P (2008). Melatonin receptors, heterodimerization, signal transduction and binding sites: what's new? Br J Pharmacol154: 1182–1195.

Pandi-Perumal SR, Srinivasan V, Maestroni GJ, Cardinali DP, Poeggeler B, Hardeland R (2006). Melatonin: Nature's most versatile biological signal? FEBS J273: 2813–2838.

Slominski A, Tobin DJ, Zmijewski MA, Wortsman J, Paus R (2008). Melatonin in the skin: synthesis, metabolism and functions. Trends Endocrinol Metab19: 17–24.