Cholecystokinin (CCK), a gastro-intestinal hormone, is secreted by intestinal I cells after the meal and regulates important digestive and metabolic functions. In pancreatic islets, CCK managed insulin secretion and beta cell mass majorly through CCK A-type receptor (CCKAR), a G protein coupled receptor, while the downstream signaling of CCKAR in pancreatic beta cells were not well defined. Here, we demonstrated that CCK-8s activated CCKAR and induced both IP3 and cAMP accumulation, which coordinately regulated efficient insulin secretion. Apart from activation of G protein signaling, CCK also promotes complex formation of CCKAR and beta-arrestin1. Exploiting RNA interference and beta-arrestin1 knockout (beta-arrestin1-/-) mice, we revealed that beta-arrestin-1 was a key mediator of both CCK promoted insulin secretion and its protective effects against apoptosis in pancreatic β cells. The anti-apoptotic effect of beta-arrestin-1 was through arrestin-mediated cytoplasmic long term ERK activation, which activates the p90RSK-phosphor-BAD antiapoptotic pathway and inhibits the caspase-3 cleavage. Further, we observed that knockdown of beta-arrestin-1 decreased both CCK-8s-induced cAMP and IP3 accumulation statistically, suggesting a crosstalk between beta-arrestin-1 and G protein mediated pathways. The importance of beta-arrestin-1 function downstream of CCKAR in pancreatic beta cells could be appreciated for development of newly anti-diabetic drugs.
37th Congress of IUPS (Birmingham, UK) (2013) Proc 37th IUPS, PCB300
Poster Communications: beta-arrestin1 mediates cholecystokinin functions in pancreatic beta cells
S. Ning1,3, N. Liang2,4, J. Su1, C. Liu1, J. Dong1,2, H. Li1, J. Sun2,4, X. Yu1,3
1. Institute of Physiology, Shandong University, School of Medicine, Jinan, Shandong, China. 2. Dept. of Biochemistry and Molecular Biology, Shandong University School of Medicine, Jinan, Shandong, China. 3. Qilu Hospital, Shandong University School of Medicine, Jinan, Shandong, China. 4. Shandong Provincial Hospital, Shandong University School of Medicine, Jinan, Shandong, China.
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Where applicable, experiments conform with Society ethical requirements.