A chemical-genetic approach to study G protein regulation of β cell function in vivo
Open Access
- 10 November 2009
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 106 (45), 19197-19202
- https://doi.org/10.1073/pnas.0906593106
Abstract
Impaired functioning of pancreatic β cells is a key hallmark of type 2 diabetes. β cell function is modulated by the actions of different classes of heterotrimeric G proteins. The functional consequences of activating specific β cell G protein signaling pathways in vivo are not well understood at present, primarily due to the fact that β 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 β cell G proteins in intact animals. Specifically, we created two lines of transgenic mice each of which expressed a specific designer GPCR in β 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 β cell Gq/11 or Gs G proteins. Here we report the findings that conditional and selective activation of β 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 β cell mass, associated with pathway-specific alterations in islet gene expression levels. Selective stimulation of β 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 β cell function in vivo.Keywords
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