RGS4 is a negative regulator of insulin release from pancreatic β-cells in vitro and in vivo

作者：Iñigo Ruı́z de Azúa, Marco Scarselli, Erica Rosemond, Dinesh Gautam, William Jou, Oksana Gavrilova, Philip J. Ebert, Pat Levitt, Jürgen Wess · 发表于：Proceedings of the National Academy of Sciences · 年份：2010 · DOI：10.1073/pnas.1003655107 · 被引用次数：93 · 研究领域：Pancreatic function and diabetes、Diabetes Treatment and Management、Metabolism, Diabetes, and Cancer

Therapeutic strategies that augment insulin release from pancreatic beta-cells are considered beneficial in the treatment of type 2 diabetes. We previously demonstrated that activation of beta-cell M(3) muscarinic receptors (M3Rs) greatly promotes glucose-stimulated insulin secretion (GSIS), suggesting that strategies aimed at enhancing signaling through beta-cell M3Rs may become therapeutically useful. M3R activation leads to the stimulation of G proteins of the G(q) family, which are under the inhibitory control of proteins known as regulators of G protein signaling (RGS proteins). At present, it remains unknown whether RGS proteins play a role in regulating insulin release. To address this issue, we initially demonstrated that MIN6 insulinoma cells express functional M3Rs and that RGS4 was by far the most abundant RGS protein expressed by these cells. Strikingly, siRNA-mediated knockdown of RGS4 expression in MIN6 cells greatly enhanced M3R-mediated augmentation of GSIS and calcium release. We obtained similar findings using pancreatic islets prepared from RGS4-deficient mice. Interestingly, RGS4 deficiency had little effect on insulin release caused by activation of other beta-cell GPCRs. Finally, treatment of mutant mice selectively lacking RGS4 in pancreatic beta-cells with a muscarinic agonist (bethanechol) led to significantly increased plasma insulin and reduced blood glucose levels, as compared to control littermates. Studies with beta-cell-specific M3R knockout mic...