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Review
. 2019 Dec 29;8(1):e00556.
doi: 10.1002/prp2.556. eCollection 2020 Feb.

The five dimensions of receptor pharmacology exemplified by melatonin receptors: An opinion

Jean A Boutin  1 , Céline Legros  2
Affiliations
Review

The five dimensions of receptor pharmacology exemplified by melatonin receptors: An opinion

Jean A Boutin et al. Pharmacol Res Perspect. .

Abstract

Receptology has been complicated with enhancements in our knowledge of G-protein-coupled-receptor (GPCR) biochemistry. This complexity is exemplified by the pharmacology of melatonin receptors. Here, we describe the complexity of GPCR biochemistry in five dimensions: (a) receptor expression, particularly in organs/tissues that are only partially understood; (b) ligands and receptor-associated proteins (interactome); (c) receptor function, which might be more complex than the known G-protein-coupled systems; (d) ligand bias, which favors a particular pathway; and (e) receptor dimerization, which might concern all receptors coexpressed in the same cell. Thus, receptor signaling might be modified or modulated, depending on the nature of the receptor complex. Fundamental studies are needed to clarify these points and find new ways to tackle receptor functionality. This opinion article emphasizes the global questions attached to new descriptions of GPCRs and aims to raise our awareness of the tremendous complexity of modern receptology.

Keywords: GPCRs; antagonism; biased ligands; dimerization; expression; interactome; melatonin; review.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Receptor functions: the functionality of a receptor depends on the associated proteins. (A) The classic downstream pathways (reproduced from the accompanying publication Legros et al57). These main signaling pathways were discovered in classical receptor studies. (B) A summary of the results of double hybrid experiments. Approximately 350 proteins were experimentally found to be associated with MT1 (left) or MT2 (right) receptors (reproduced with permission from Benleulmi‐Chaachoua et al,39). The original figure legend applies here: “Melatonin receptor network, based on 20 different screens. Identified proteins are clustered based on the detection method used. Edge colors identify the identification methods applied as defined: dark blue for the MYTH, blue for Cter peptide purification, green for the Y2H, and brown for the TAP. Thick lines correspond to confirmed protein‐protein interactions (PPIs) and node colors refer to Gene Ontology (GO) biological function. The network contains 366 interacting partners of which 168, 143, and 52 are specific for MT1, MT2, or common for both receptors, respectively. Additional interactions and partners were added from the Interologou Interaction Database I2D Ver. 2.3. The network is visualized using NAViGaTOR 2.3.1 tools (http://ophid.utoronto.ca/navigator). Classifications of PPIs of the MT1 and MT2 receptor interactomes depend on GO entries”
Figure 2
Figure 2
Biased ligand radar‐plot representations of melatonin receptor agonists. Data represent ΔLog(max/EC50) values, typically relevant from biased pharmacology57 which compare the agonism of the compound to the agonism of melatonin for the particular signaling pathway. The set of ligands comprised 19 ligands, including melatonin. (A) MT1 receptor; (B) MT2 receptor. The traces are color‐coded as follows: green = GTPγS; blue = β‐arrestin; pink = internalization; red = cAMP; and black = Cellkey® (reproduced from the accompanying publication57)
See this image and copyright information in PMC

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