Differential contributions of G protein- or arrestin subtype-mediated signalling underlie urocortin 3-induced somatostatin secretion in pancreatic δ cells

Background and purpose: Pancreatic islets are modulated by cross-talk among different cell types and paracrine signalling plays important roles in maintaining glucose homeostasis. Urocortin 3 (UCN3) secreted by pancreatic β cells activates the CRF₂ receptor (CRF₂R) and downstream pathways mediated by different G protein or arrestin subtypes in δ cells to cause somatostatin (SST) secretion, and constitutes an important feedback circuit for glucose homeostasis.

Experimental approach: Here, we used Arrb1^-/-, Arrb2^-/-, Gs^fl/fl and Gq^fl/fl knockout mice, the G₁₁-shRNA-GFP^fl/fl lentivirus, as well as functional assays and pharmacological characterization to study how the coupling of G_s, G₁₁ and β-arrestin1 to CRF₂R contributed to UCN3-induced SST secretion in pancreatic δ cells.

Key results: Our study showed that CRF₂R coupled to a panel of G protein and arrestin subtypes in response to UCN3 engagement. While RyR3 phosphorylation by PKA at the S156, S2706 and S4697 sites may underlie the Gs-mediated UCN3- CRF₂R axis for SST secretion, the interaction of SYT1 with β-arrestin1 is also essential for efficient SST secretion downstream of CRF₂R. The specific expression of the transcription factor Stat6 may contribute to G₁₁ expression in pancreatic δ cells. Furthermore, we found that different UCN3 concentrations may have distinct effects on glucose homeostasis, and these effects may depend on different CRF₂R downstream effectors.

Conclusions and implications: Collectively, our results provide a landscape view of signalling mediated by different G protein or arrestin subtypes downstream of paracrine UCN3- CRF₂R signalling in pancreatic β-δ-cell circuits, which may facilitate the understanding of fine-tuned glucose homeostasis networks.