Melatonin receptors: molecular pharmacology and signalling in the context of system bias

Abstract

Melatonin, N-acetyl-5-methoxytryptamine, an evolutionally old molecule, is produced by the pineal gland in vertebrates, and it binds with high affinity to melatonin receptors, which are members of the GPCR family. Among the multiple effects attributed to melatonin, we will focus here on those that are dependent on the activation of the two mammalian MT and MT melatonin receptors. We briefly summarize the latest developments on synthetic melatonin receptor ligands, including multi-target-directed ligands, and the characterization of signalling-biased ligands. We discuss signalling pathways activated by melatonin receptors that appear to be highly cell- and tissue-dependent, emphasizing the impact of system bias on the functional outcome. Different proteins have been demonstrated to interact with melatonin receptors, and thus, we postulate that part of this system bias has its molecular basis in differences of the expression of receptor-associated proteins including heterodimerization partners. Finally, bias at the level of the receptor, by the expression of genetic receptor variants, will be discussed to show how a modified receptor function can have an effect on the risk for common diseases like type 2 diabetes in humans.

Pathophysiology of Depression: Molecular Regulation of Melatonin Homeostasis – Current Status

“…Both receptors are G-coupled 7-transmembrane receptors [33]. For a more detailed description of melatonin receptor signaling pathways, the reader is referred to other expert reviewers [34, 35]. In short, both receptors are tightly coupled to the Gi/cAMP pathway.…”

“…Cecon et al [34] prepared lists of human tissues in which melatonin receptors have been identified. Thus melatonin, via MT 1 and MT 2 receptors, regulates a variety of physiological and neuroendocrine functions.…”

Melatonin attenuates smoking‐induced hyperglycemia via preserving insulin secretion and hepatic glycogen synthesis in rats

“…Many of melatonin's biological effects are mediated by the activation of melatonin receptors . The effects of melatonin are mediated by two receptors, which are expressed in a function‐specific fashion . The melatonin receptors of β cells positively regulate cellular functions and affect insulin secretion in the subtype‐dependent mode .…”

Recent developments in research of melatonin and its potential therapeutic applications

“…In their review, Cecon et al (2018) make a gentle start by explaining that MT 1 and MT 2 receptors are both GPCRs, with several coupling targets, before going on to outline their distribution, structure, function and pharmacology. The authors then discuss the possibility of developing multi-target-directed, 'hybrid ligands', which combine melatonin with other drugs, to achieve additive therapeutic effects.…”

“…Environmental differences include cell type; cell context-dependent receptor expression; receptor homo and heterodimerization; and even features of the lipid membrane. These variables also influence epigenetic responses to melatonin, and Cecon et al (2018) suggest that this could explain why the effects of melatonin on circadian clock gene expression depend on cell type. However, the coup de grace is the evidence that over 300 different proteins interact with the MT 1 receptor and only about 50 of them overlap with proteins that interact with the MT 2 receptor.…”