THESIS
2022
1 online resource (xii, 144 pages) : illustrations (some color)
Abstract
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 MT
1 and MT
2. The melatonin receptor-mediated pathways were found to exert
numerous beneficial effects on circadian rhythm, neuroprotection, learning and memory, and
cancer. Co-localization of MT
1 and MT
2 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 MT
1 and MT
2 was reported, the signaling characteristics and t...[
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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 MT
1 and MT
2. The melatonin receptor-mediated pathways were found to exert
numerous beneficial effects on circadian rhythm, neuroprotection, learning and memory, and
cancer. Co-localization of MT
1 and MT
2 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 MT
1 and MT
2 was reported, the signaling characteristics and the structural basis of
the MT
1/MT
2 heterodimer remain poorly understood. To further study the signaling mechanism
of the MT
1/MT
2 heterodimers, the intrinsic differences in signaling pathways between MT
1
and MT
2 were first examined, followed by the characterization of the pharmacological profiles
and signal transduction mechanism of the MT
1/MT
2 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. MT
1 but not MT
2 can
further activate the G
s pathway upon melatonin stimulation. Pharmacological profiles of MT
1
and MT
2 homo- and heterodimers were generated by Ca
2+ mobilization assays, revealing that
MT
1 receptor appeared to be the predominant functional unit of the MT
1/MT
2 heteromer.
R
3.50mutations and β-arrestin recruitment assays further demonstrated a preferred interaction
of downstream effectors towards MT
1 in the MT
1/MT
2 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 MT
1/MT
2 heterodimer formation. Further studies on MT
1/MT
2 heterodimer may provide clues for
examining the complex regulatory mechanisms of melatonin with the ultimate goal of
developing new therapeutic agents.
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