Update on melatonin receptors: IUPHAR Review 20

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.

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

Structures of MT₂ receptor‐selective ligands. BOMPPA, benzyloxy‐methoxyphenyl‐propylamide; CIFEA, cyclohexylmethyl‐indenofurane‐ethylacetamide; 4P‐PDOT, 4‐phenyl‐2‐propionamidotetralin.

Figure 3

Structures of MT₁ receptor‐selective ligands. CBOBNEA, carboxybiphenyloxy‐butoxy‐naphthalene‐ethylacetamide; AAE‐M‐PBP amine, acetylaminoethyl‐methyl‐phenylbutoxyphenyl‐amine.

Figure 4

Structures of radioligands used to determine binding affinity for MT₁ and MT₂ receptors.

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 MT₁*‐MLT (A) was derived from active forms of rhodopsin, β₂‐adrenoceptor and A_2A adenosine receptors (unpublished data, N.R.).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‐Gα_s structure (Rasmussen et al., 2011b) and the homology between Gα_s 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

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 ^3.49NRY^3.51 motif and the ^7.49NAXXY^7.53 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.