期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2009
卷号：106
期号：45
页码：19197-19202
DOI：10.1073/pnas.0906593106
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Impaired functioning of pancreatic {beta} cells is a key hallmark of type 2 diabetes. {beta} cell function is modulated by the actions of different classes of heterotrimeric G proteins. The functional consequences of activating specific {beta} cell G protein signaling pathways in vivo are not well understood at present, primarily due to the fact that {beta} cell G protein-coupled receptors (GPCRs) are also expressed by many other tissues. To circumvent these difficulties, we developed a chemical-genetic approach that allows for the conditional and selective activation of specific {beta} cell G proteins in intact animals. Specifically, we created two lines of transgenic mice each of which expressed a specific designer GPCR in {beta} cells only. Importantly, the two designer receptors differed in their G protein-coupling properties (Gq/11 versus Gs). They were unable to bind endogenous ligand(s), but could be efficiently activated by an otherwise pharmacologically inert compound (clozapine-N-oxide), leading to the conditional activation of either {beta} cell Gq/11 or Gs G proteins. Here we report the findings that conditional and selective activation of {beta} cell Gq/11 signaling in vivo leads to striking increases in both first- and second-phase insulin release, greatly improved glucose tolerance in obese, insulin-resistant mice, and elevated {beta} cell mass, associated with pathway-specific alterations in islet gene expression levels. Selective stimulation of {beta} cell Gs triggered qualitatively similar in vivo metabolic effects. Thus, this developed chemical-genetic strategy represents a powerful approach to study G protein regulation of {beta} cell function in vivo.
关键词：beta cells ; G protein-coupled receptors ; transgenic mice ; type 2 diabetes
