Type 2 diabetes–associated variants of the MT 2 melatonin receptor affect distinct modes of signaling

Angeliki Karamitri, Bianca Plouffe, Amélie Bonnefond, Min Chen, Jonathan Gallion, Jean Luc Guillaume, Alan Hegron, Mathilde Boissel, Mickaël Canouil, Claudia Langenberg, Nicholas J. Wareham, Christian Le Gouill, Viktoria Lukasheva, Olivier Lichtarge, Philippe Froguel, Michel Bouvier, Ralf Jockers*

*Corresponding author for this work

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15 Citations (Scopus)

Abstract

Melatonin is produced during the night and regulates sleep and circadian rhythms. Loss-of-function variants in MTNR1B, which encodes the melatonin receptor MT 2 , 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 MT 2 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 G i1 and G z proteins and in spontaneous-arrestin2 recruitment to MT 2 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 intervention and reveals the potential relevance of MT 2 function during the day, when melatonin is undetectable, but spontaneous activity of the receptor occurs.

Original languageEnglish
Article numbereaan6622
Number of pages14
JournalScience Signaling
Volume11
Issue number545
DOIs
Publication statusPublished - 28 Aug 2018

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Karamitri, A., Plouffe, B., Bonnefond, A., Chen, M., Gallion, J., Guillaume, J. L., Hegron, A., Boissel, M., Canouil, M., Langenberg, C., Wareham, N. J., Le Gouill, C., Lukasheva, V., Lichtarge, O., Froguel, P., Bouvier, M., & Jockers, R. (2018). Type 2 diabetes–associated variants of the MT 2 melatonin receptor affect distinct modes of signaling. Science Signaling, 11(545), [eaan6622]. https://doi.org/10.1126/scisignal.aan6622