Article Dans Une Revue PLoS ONE Année : 2021

Neuromedin U uses Gαi2 and Gαo to suppress glucose-stimulated Ca2+ signaling and insulin secretion in pancreatic β cells.

Résumé

Neuromedin U (NMU), a highly conserved peptide in mammals, is involved in a wide variety of physiological processes, including impairment of pancreatic β-cell function via induction of mitochondrial dysfunction and endoplasmic reticulum (ER) stress, ultimately suppressing insulin secretion. NMU has two receptors, NMU receptor 1 (NMUR1) and NMUR2, both of which are G-protein–coupled receptors (GPCRs). Only NMUR1 is expressed in mouse islets and β cell–derived MIN6-K8 cells. The molecular mechanisms underlying the insulinostatic action mediated by NMUR1 in β cells have yet to be elucidated. In this study, we explored the molecular mechanism driving impairment of insulin secretion in β cells by the NMU–NMUR1 axis. Pretreatment with the Gαi/o inhibitor Bordetella pertussis toxin (PTX), but not the Gαq inhibitor YM254890, abolished NMU-induced suppression of glucose-stimulated insulin secretion and calcium response in β cells. Knockdown of Gαi2 and Gαo in β cells counteracted NMU-induced suppression of insulin secretion and gene alterations related to mitochondrial fusion (Mfn1, Mfn2), fission (Fis1, Drp1), mitophagy (Pink1, Park2), mitochondrial dynamics (Pgc-1α, Nrf1, and Tfam), ER stress (Chop, Atp2a3, Ryr2, and Itpr2), intracellular ATP level, and mitochondrial membrane potential. NMU decreased forskolin-stimulated intracellular cAMP in both mouse and human islets. We concluded that NMUR1 coupled to PTX-sensitive Gαi2 and Gαo proteins in β cells reduced intracellular Ca2+ influx and cAMP level, thereby causing β-cell dysfunction and impairment. These results highlight a novel signaling mechanism of NMU and provide valuable insights into the further investigation of NMU functions in β-cell biology.
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hal-04737978 , version 1 (15-10-2024)

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Weidong Zhang, Hideyuki Sakoda, Yuki Nakazato, Md Nurul Islam, Francois Pattou, et al.. Neuromedin U uses Gαi2 and Gαo to suppress glucose-stimulated Ca2+ signaling and insulin secretion in pancreatic β cells.. PLoS ONE, 2021, PLoS ONE, 16 (4), pp.e0250232. ⟨10.1371/journal.pone.0250232⟩. ⟨hal-04737978⟩
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