Beta-arrestin2 is essential for the proper function of pancreatic beta cells

FARE Award Winner

Authors

• L Zhu
• J Wess

Abstract

Beta-arrestins (barr1 and barr2) are G protein-coupled receptor (GPCR)-associated proteins that function to dampen GPCR signaling but can also act as scaffolding proteins to facilitate G protein-independent signaling. Studies with whole body barr2 KO mice have shown that barr2 plays a critical role in maintaining euglycemia. However, it remains unclear which specific cell types and signaling pathways are involved in this phenomenon. To investigate the function of barr2 in pancreatic beta cells, we generated beta cell-specific barr2 knockout mice (beta-barr2 KO mice). Studies with barr2-deficient islets showed that glucose- and KCl-stimulated insulin release and increases in intracellular calcium levels were greatly reduced in the mutant islets. Beta-barr2 KO mice on a HFD showed greatly reduced glucose tolerance, associated with a reduction in insulin secretion. We also examined whether barr2 is required for CAMKII function in beta cells. Treatment of WT islets with a CaMKII inhibitor (AIP2) led to similar deficits in insulin secretion and calcium influx as observed with beta-barr2 KO mice. Expression of a constitutively active version of CaMKII in MIN6 cells fully rescued the deficits in insulin secretion observed after barr2 knockdown. Taken together, these observations strongly suggest that barr2 is required for CAMKII activity in beta cells, probably by acting as a scaffolding protein for CAMKII. Our findings convincingly demonstrate that barr2 is essential for the proper function of pancreatic beta cells. Strategies aimed at enhancing barr2 activity in pancreatic beta cells may prove useful to improve beta cell function for therapeutic purposes.

Scientific Focus Area: Cell Biology

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