Transgenic Mice Expressing CNO-sensitive Gq- or Gs-coupled Designer Receptors Selectively in Pancreatic Beta Cells

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 strategy 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 (DREADD = Designer Receptor Exclusively Activated by a Designer Drug) in beta cells only (beta-RASSL-1 = RIPII-Rq Tg = beta Gq DREADD transgenic mice; beta-RASSL-2 = RIPII-Rs = beta Gs DREADD transgenic mice). Importantly, the two designer receptors differ in their G protein-coupling properties (Gq versus Gs). They are unable to bind endogenous ligand(s), but can be efficiently activated by an otherwise pharmacologically inert compound (clozapine-N-oxide = CNO), leading to the conditional activation of either beta cell Gq or Gs G proteins. These newly developed transgenic mice represent powerful new tools to study G protein regulation of beta cell function in vivo.