MELATONIN TARGET PROTEINS: INTERACTIONS AND FUNCTIONS

Abstract

Melatonin (N-acetyl-5-methoxytryptamine) is the primary hormone of the pineal gland, however its synthesis also occurs in various extrapineal tissues, including the brain, retina, retinal pigment epithelium, gastrointestinal tract, bone marrow, thymus, lymphocytes, and skin. Melatonin is an amphiphilic indole derivative that combines hydrophilic (methyl and amide groups) and hydrophobic (indole core) molecular domains. Due to its unique structure, which ensures high bioavailability, and the presence of the hormone and enzymatic mechanisms for its synthesis in various organs and tissues, melatonin is involved in regulating numerous physiological processes, highlighting its significant role in maintaining systemic homeostasis. The pleiotropic effects of melatonin are due to a combination of its direct molecular interactions and mediated regulatory mechanisms. On the one hand, melatonin exhibits the properties of a powerful endogenous antioxidant capable of directly neutralizing reactive oxygen and nitrogen species. On the other hand, its physiological effects are realized through binding to specific protein targets, as well as through secondary mechanisms, including the activation of antioxidant defense, metabolic, and epigenetic modulation. Of particular interest is the interaction of the hormone with numerous extracellular and intracellular molecular targets, with binding affinity varying across a wide range of concentrations. Research over recent decades has identified approximately twenty distinct protein targets of melatonin, spanning a broad spectrum of functional categories - from well-characterized receptors (membrane-bound and nuclear) to non-canonical targets. These include: enzymes (quinone reductase 2, matrix metalloproteinase-9, protein phosphatase 2A, pepsin), ion channels, transport and structural proteins (glucose transporter GLUT1, oligopeptide transporters PEPT1 and PEPT2, serum albumin, tubulin), calcium-binding proteins (calmodulin, protein kinase C, calreticulin). The search for melatonin targets continues. It is hypothesized that, in addition to its mediated effects, the hormone may directly modulate the activity of the membrane resistance protein P-glycoprotein and NAD⁺-dependent deacetylases – sirtuins SIRT1 and SIRT3.

Conclusions. Studying melatonin targets is crucial for analyzing its pharmacodynamic effects, while the search for new targets opens perspectives for understanding the hormone’s non-circadian functions, such as neuroprotection, anticancer effects, and metabolic modulation.