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Review
. 2016 Sep;173(18):2702-25.
doi: 10.1111/bph.13536. Epub 2016 Aug 8.

Update on melatonin receptors: IUPHAR Review 20

Ralf Jockers  1   2   3 , Philippe Delagrange  4 , Margarita L Dubocovich  5 , Regina P Markus  6 , Nicolas Renault  7 , Gianluca Tosini  8 , Erika Cecon  1   2   3 , Darius P Zlotos  9
Affiliations
Review

Update on melatonin receptors: IUPHAR Review 20

Ralf Jockers et al. Br J Pharmacol. 2016 Sep.

Abstract

Melatonin receptors are seven transmembrane-spanning proteins belonging to the GPCR superfamily. In mammals, two melatonin receptor subtypes exist - MT1 and MT2 - encoded by the MTNR1A and MTNR1B genes respectively. The current review provides an update on melatonin receptors by the corresponding subcommittee of the International Union of Basic and Clinical Pharmacology. We will highlight recent developments of melatonin receptor ligands, including radioligands, and give an update on the latest phenotyping results of melatonin receptor knockout mice. The current status and perspectives of the structure of melatonin receptor will be summarized. The physiological importance of melatonin receptor dimers and biologically important and type 2 diabetes-associated genetic variants of melatonin receptors will be discussed. The role of melatonin receptors in physiology and disease will be further exemplified by their functions in the immune system and the CNS. Finally, antioxidant and free radical scavenger properties of melatonin and its relation to melatonin receptors will be critically addressed.

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Figures

Figure 1
Figure 1
Structures of non‐selective MT1/MT2 receptor ligands. 5‐HEAT, 5‐hydroxyethoxy‐N‐acetyltryptamine; EFPPEA, ethyl‐furo‐pyrazolo‐pyridine‐ethyl‐acetamide.
Figure 2
Figure 2
Structures of MT2 receptor‐selective ligands. BOMPPA, benzyloxy‐methoxyphenyl‐propylamide; CIFEA, cyclohexylmethyl‐indenofurane‐ethylacetamide; 4P‐PDOT, 4‐phenyl‐2‐propionamidotetralin.
Figure 3
Figure 3
Structures of MT1 receptor‐selective ligands. CBOBNEA, carboxybiphenyloxy‐butoxy‐naphthalene‐ethylacetamide; AAE‐M‐PBP amine, acetylaminoethyl‐methyl‐phenylbutoxyphenyl‐amine.
Figure 4
Figure 4
Structures of radioligands used to determine binding affinity for MT1 and MT2 receptors.
Figure 5
Figure 5
Structures useful for the study of MT1 receptor structure–function relationships. MT1*‐MLT (A) was derived from active forms of rhodopsin, β2‐adrenoceptor and A2A adenosine receptors (unpublished data, N.R.). Docking of melatonin (MLT) in the solvent‐accessible cavity was achieved by energy relaxation by 300‐ns molecular dynamics simulations. The structure of the MT1*‐MLT‐Giα3 complex could be modelled on the basis of the sequence homology with the β2‐adrenoceptor‐Gαs structure (Rasmussen et al., 2011b) and the homology between Gαs and Giα3 (Soundararajan et al., 2008) (B) whereas the structure of the MT1*‐MLT‐arrestin complex could be modelled based on the crystallized rhodopsin‐arrestin complex (Kang et al., 2015) (C).
Figure 6
Figure 6
Distribution of non‐synonymous MT1 (A) and MT2 (B) receptor variants identified in various human populations. Positions of variants are highlighted in light brown. Typical signatures of MT receptors such as the 3.49NRY3.51 motif and the 7.49NAXXY7.53 motif are highlighted in red. Residues suspected to be directly involved in melatonin binding (S3.35 and S3.39 in MT1 and H5.46 in both MT1 and MT2 receptors) are highlighted with a blue circle. The putative palmitoylation site at C314 is indicated in MT1 receptors.
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