Melatonin is a hormone of sleep that regulates a variety of physiological and neuroendocrine functions in adjustment to the light-dark cycle. The functional responses of melatonin are mainly mediated through the activation of two G protein-coupled receptors, named melatonin receptors MT₁ and MT₂. The melatonin receptor-mediated pathways were found to exert numerous beneficial effects on circadian rhythm, neuroprotection, learning and memory, and cancer. Co-localization of MT₁ and MT₂ has been reported in many types of tissues, including the cerebral cortex, basal forebrain, retina, and pancreatic islet. Although the biological importance of each melatonin receptor subtype has been well studied and the heteromerization between MT₁ and MT₂ was reported, the signaling characteristics and t...[ Read more ]

Melatonin is a hormone of sleep that regulates a variety of physiological and neuroendocrine functions in adjustment to the light-dark cycle. The functional responses of melatonin are mainly mediated through the activation of two G protein-coupled receptors, named melatonin receptors MT₁ and MT₂. The melatonin receptor-mediated pathways were found to exert numerous beneficial effects on circadian rhythm, neuroprotection, learning and memory, and cancer. Co-localization of MT₁ and MT₂ has been reported in many types of tissues, including the cerebral cortex, basal forebrain, retina, and pancreatic islet. Although the biological importance of each melatonin receptor subtype has been well studied and the heteromerization between MT₁ and MT₂ was reported, the signaling characteristics and the structural basis of the MT₁/MT₂ heterodimer remain poorly understood. To further study the signaling mechanism of the MT₁/MT₂ heterodimers, the intrinsic differences in signaling pathways between MT₁ and MT₂ were first examined, followed by the characterization of the pharmacological profiles and signal transduction mechanism of the MT₁/MT₂ heterodimer. Computational modeling was further applied to provide the structural understanding of receptor dimerization. cAMP assays revealed spontaneous G_i signaling properties of melatonin receptors. MT₁ but not MT₂ can further activate the G_s pathway upon melatonin stimulation. Pharmacological profiles of MT₁ and MT₂ homo- and heterodimers were generated by Ca²⁺ mobilization assays, revealing that MT₁ receptor appeared to be the predominant functional unit of the MT₁/MT₂ heteromer. R^3.50mutations and β-arrestin recruitment assays further demonstrated a preferred interaction of downstream effectors towards MT₁ in the MT₁/MT₂ heterodimer. Rosetta MP docking was conducted to generate models for all the reported heterodimers of melatonin receptors. Mutagenesis of the predicted interface residues has successfully disrupted the MT₁/MT₂ heterodimer formation. Further studies on MT₁/MT₂ heterodimer may provide clues for examining the complex regulatory mechanisms of melatonin with the ultimate goal of developing new therapeutic agents.