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

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 Gα i/o inhibitor Bordetella pertussis toxin (PTX), but not the Gα q inhibitor YM254890, abolished NMU-induced suppression of glucose-stimulated insulin secretion and calcium response in β cells. Knockdown of Gα i2 and Gα o 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 Gα i2 and Gα o proteins in β cells reduced intracellular Ca 2+ 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.