Type 2 diabetes-associated variants of the MT2 melatonin receptor affect distinct modes of signaling.

Science Signaling
Angeliki KaramitriRalf Jockers

Abstract

Melatonin is produced during the night and regulates sleep and circadian rhythms. Loss-of-function variants in MTNR1B, which encodes the melatonin receptor MT2, a G protein-coupled receptor (GPCR), are associated with an increased risk of type 2 diabetes (T2D). To identify specific T2D-associated signaling pathway(s), we profiled the signaling output of 40 MT2 variants by monitoring spontaneous (ligand-independent) and melatonin-induced activation of multiple signaling effectors. Genetic association analysis showed that defects in the melatonin-induced activation of Gαi1 and Gαz proteins and in spontaneous β-arrestin2 recruitment to MT2 were the most statistically significantly associated with an increased T2D risk. Computational variant impact prediction by in silico evolutionary lineage analysis strongly correlated with the measured phenotypic effect of each variant, providing a predictive tool for future studies on GPCR variants. Together, this large-scale functional study provides an operational framework for the postgenomic analysis of the multiple GPCR variants present in the human population. The association of T2D risk with signaling pathway-specific defects opens avenues for pathway-specific personalized therapeutic in...Continue Reading

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Citations

Aug 15, 2018·Nature Reviews. Molecular Cell Biology·Denise WoottenPatrick M Sexton
Oct 12, 2018·Proceedings of the National Academy of Sciences of the United States of America·Franziska MendeBirgitte Holst
Apr 11, 2019·Journal of Pineal Research·Daniella BuonfiglioGianluca Tosini
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Aug 6, 2019·Frontiers in Endocrinology·Sharon OwinoGianluca Tosini
Dec 12, 2018·Nature Reviews. Endocrinology·Angeliki Karamitri, Ralf Jockers
Apr 18, 2019·Nature Chemical Biology·Daniele BologniniGraeme Milligan
Oct 14, 2020·Biology of Reproduction·Violetta LozovyyRamkumar Menon
Dec 18, 2020·Journal of Pineal Research·Erika CeconRalf Jockers
Nov 7, 2020·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Romain GerbierRalf Jockers
Oct 26, 2021·Frontiers in Cellular Neuroscience·Lap Hang Tse, Yung Hou Wong

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