Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2021 Sep 26;9(4):67.
doi: 10.3390/diseases9040067.

Empowering Melatonin Therapeutics with Drosophila Models

Cassandra Millet-Boureima  1 , Caroline C Ennis  2 , Jurnee Jamison  2 , Shana McSweeney  2 , Anna Park  2 , Chiara Gamberi  2
Affiliations
Review

Empowering Melatonin Therapeutics with Drosophila Models

Cassandra Millet-Boureima et al. Diseases. .

Abstract

Melatonin functions as a central regulator of cell and organismal function as well as a neurohormone involved in several processes, e.g., the regulation of the circadian rhythm, sleep, aging, oxidative response, and more. As such, it holds immense pharmacological potential. Receptor-mediated melatonin function mainly occurs through MT1 and MT2, conserved amongst mammals. Other melatonin-binding proteins exist. Non-receptor-mediated activities involve regulating the mitochondrial function and antioxidant cascade, which are frequently affected by normal aging as well as disease. Several pathologies display diseased or dysfunctional mitochondria, suggesting melatonin may be used therapeutically. Drosophila models have extensively been employed to study disease pathogenesis and discover new drugs. Here, we review the multiple functions of melatonin through the lens of functional conservation and model organism research to empower potential melatonin therapeutics to treat neurodegenerative and renal diseases.

Keywords: Drosophila; PKD; longevity; melatonin; neurodegeneration; oxidative stress.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The melatonin signaling cascades. Melatonin binds to transmembrane receptors MT1 and MT2, as well as the MT3 binding site on the cytosolic enzyme QR2, and, possibly, the nuclear receptor RZR/RORα. Melatonin (ligand) binding with MT1 and MT2 receptors recruits β-arrestin and activates G proteins, which inhibit adenylyl cyclase activity and decrease cAMP levels. MT1 coupling to G proteins activates phospholipase C (PLC), which leads to increased intracellular Ca2+. Melatonin-dependent activation of MT2 and associated G proteins prompts interaction with guanylyl cyclase, which reduces cGMP levels; therefore, lowering PKG activity. In vertebrates, except for birds and fish [42,141], heteromerization of GPR50 and MT1 (but not MT2) inhibits both G protein interactions and melatonin binding. Melatonin acts as a ligand for MT3 and, possibly, for RORα, independently of the MT1 and MT2 pathways. With RORα and RORγ, melatonin affects nuclear transcription factor activity and gene expression.
Figure 2
Figure 2
Simplified melatonin antioxidant cascade (drawn after [163]).
See this image and copyright information in PMC

References

    1. Chowdhury I., Sengupta A., Maitra S.K. Melatonin: Fifty years of scientific journey from the discovery in bovine pineal gland to delineation of functions in human. Ind. J. Biochem. Biophys. 2008;45:289–304. - PubMed
    1. Zhao D., Yu Y., Shen Y., Liu Q., Zhao Z., Sharma R., Reiter R.J. Melatonin synthesis and function: Evolutionary history in animals and plants. Front. Endocrinol. 2019;10:249. doi: 10.3389/fendo.2019.00249. - DOI - PMC - PubMed
    1. Lerner A.B., Case J.D., Takahashi Y., Lee T.H., Mori W. Isolation of melatonin, the pineal gland factor that lightens melanocytes. J. Am. Chem. Soc. 1958;80:2587. doi: 10.1021/ja01543a060. - DOI
    1. Dubbels R., Reiter R.J., Klenke E., Goebel A., Schnakenberg E., Ehlers C., Schiwara H.W., Schloot W. Melatonin in edible plants identified by radioimmunoassay and by high performance liquid chromatography-mass spectrometry. J. Pineal Res. 1995;18:28–31. doi: 10.1111/j.1600-079X.1995.tb00136.x. - DOI - PubMed
    1. Hattori A., Migitaka H., Iigo M., Itoh M., Yamamoto K., Ohtani-Kaneko R., Hara M., Suzuki T., Reiter R.J. Identification of melatonin in plants and its effects on plasma melatonin levels and binding to melatonin receptors in vertebrates. Biochem. Mol. Biol. Int. 1995;35:627–634. - PubMed

LinkOut - more resources