| First Author | Wang KY | Year | 2024 |
| Journal | Br J Pharmacol | Volume | 181 |
| Issue | 15 | Pages | 2600-2621 |
| PubMed ID | 38613153 | Mgi Jnum | J:359485 |
| Mgi Id | MGI:7788296 | Doi | 10.1111/bph.16351 |
| Citation | Wang KY, et al. (2024) Differential contributions of G protein- or arrestin subtype-mediated signalling underlie urocortin 3-induced somatostatin secretion in pancreatic delta cells. Br J Pharmacol 181(15):2600-2621 |
| abstractText | 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 beta cells activates the CRF(2) receptor (CRF(2)R) and downstream pathways mediated by different G protein or arrestin subtypes in delta 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 G(11)-shRNA-GFP(fl/fl) lentivirus, as well as functional assays and pharmacological characterization to study how the coupling of G(s), G(11) and beta-arrestin1 to CRF(2)R contributed to UCN3-induced SST secretion in pancreatic delta cells. KEY RESULTS: Our study showed that CRF(2)R 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- CRF(2)R axis for SST secretion, the interaction of SYT1 with beta-arrestin1 is also essential for efficient SST secretion downstream of CRF(2)R. The specific expression of the transcription factor Stat6 may contribute to G(11) expression in pancreatic delta cells. Furthermore, we found that different UCN3 concentrations may have distinct effects on glucose homeostasis, and these effects may depend on different CRF(2)R 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- CRF(2)R signalling in pancreatic beta-delta-cell circuits, which may facilitate the understanding of fine-tuned glucose homeostasis networks. |
