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

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.

Melatonin MT1 and MT2 receptor ERK signaling is differentially dependent on Gi/o and Gq/11 proteins

“…Responses to melatonin are highly context‐dependent . This is nicely illustrated by the G q ‐dependent signaling events that have been observed in some but not all cell types and tissues .…”

“…Signal transduction occurs through inhibition of cAMP and cGMP production, activation of extracellular signal‐regulated kinase 1/2 (ERK1/2) and ion channels . Some intrinsic differences in the signaling capacity of MT 1 and MT 2 are documented, such as the modulation of the cGMP pathway that is only observed for MT 2 , but most of the differences appear to depend on the cellular context and on the formation of receptor‐specific signaling complexes …”

Melatonin receptor ligands: A pharmaco‐chemical perspective

“…As previously mentioned, 18 the landscape of receptor molecular pharmacology—particularly melatonin receptors—became even more complex due to the lack of selective antibodies (until recently 156 ) and the complex nature of biasism 19 . The melatonin receptor crystallization works of Stauch et al on MT 1 125 and of Johansson et al on MT 2 126 open new and exciting avenues of research regarding this bicycle motto, which has already begun 135,136 …”

“…Finally, at the basis of these discoveries is the notion of agonism and antagonism. In both cases, one must understand that the ways GPCRs signal within cells are more complex than initially suggested (see Boutin & Legros, 18 for discussion). Indeed, biased agonists and antagonists have emerged and demonstrate that one compound can antagonize one intracellular signaling pathway while displaying agonist actions at another 19 .…”

Biased Ligands Differentially Shape the Conformation of the Extracellular Loop Region in 5-HT2B Receptors

“…G protein-coupled receptors (GPCRs) are involved in the regulation of a plethora of physiological processes, and about 35% of currently marketed therapeutics directly target GPCRs [ 1 ]. In the last decade, structural and biophysical data helped to revisit our understanding of GPCR activation and revealed a surprisingly complex pharmacology [ 2 ] including several dimensions of spatiotemporal signaling [ 3 , 4 , 5 , 6 , 7 , 8 ]. One important aspect of this complexity is the preference of a certain ligand–receptor complex for one intracellular transducer protein over another, commonly referred to as biased signaling or functional selectivity [ 9 ].…”