In:
British Journal of Pharmacology, Wiley, Vol. 172, No. 21 ( 2015-11), p. 5050-5067
Kurzfassung:
Cholecystokinin (CCK) is secreted by intestinal I cells and regulates important metabolic functions. In pancreatic islets, CCK controls beta cell functions primarily through CCK 1 receptors, but the signalling pathways downstream of these receptors in pancreatic beta cells are not well defined. Experimental Approach Apoptosis in pancreatic beta cell apoptosis was evaluated using Hoechst‐33342 staining, TUNEL assays and Annexin‐V‐FITC/PI staining. Insulin secretion and second messenger production were monitored using ELISAs. Protein and phospho‐protein levels were determined by Western blotting. A glucose tolerance test was carried out to examine the functions of CCK‐8s in streptozotocin‐induced diabetic mice. Key Results The sulfated carboxy‐terminal octapeptide CCK 26‐33 amide (CCK‐8s) activated CCK 1 receptors and induced accumulation of both IP 3 and cAMP. Whereas G q ‐PLC‐IP 3 signalling was required for the CCK‐8s‐induced insulin secretion under low‐glucose conditions, G s ‐PKA/Epac signalling contributed more strongly to the CCK‐8s‐mediated insulin secretion in high‐glucose conditions. CCK‐8s also promoted formation of the CCK 1 receptor/β‐arrestin‐1 complex in pancreatic beta cells. Using β‐arrestin‐1 knockout mice, we demonstrated that β‐arrestin‐1 is a key mediator of both CCK‐8s‐mediated insulin secretion and of its the protective effect against apoptosis in pancreatic beta cells. The anti‐apoptotic effects of β‐arrestin‐1 occurred through cytoplasmic late‐phase ERK activation, which activates the 90‐kDa ribosomal S6 kinase‐phospho–Bcl‐2‐family protein pathway. Conclusions and Implications Knowledge of different CCK 1 receptor‐activated downstream signalling pathways in the regulation of distinct functions of pancreatic beta cells could be used to identify biased CCK 1 receptor ligands for the development of new anti‐diabetic drugs.
Materialart:
Online-Ressource
ISSN:
0007-1188
,
1476-5381
DOI:
10.1111/bph.2015.172.issue-21
Sprache:
Englisch
Verlag:
Wiley
Publikationsdatum:
2015
ZDB Id:
2029728-2
SSG:
15,3
