title: Different downstream signalling of CCK1 receptors regulates distinct functions of CCK in pancreatic beta cells.
abstract: OBJECTIVE
  Cholecystokinin (CCK) is secreted by intestinal I cells and regulates important metabolic functions. In pancreatic islets, CCK controls beta cell functions primarily through CCK1 receptors, but the signalling pathways downstream of these receptors in pancreatic beta cells are not well defined.
  
  
  METHODS
  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.
  
  
  RESULTS
  The sulfated carboxy-terminal octapeptide CCK26-33 amide (CCK-8s) activated CCK1 receptors and induced accumulation of both IP3 and cAMP. Whereas Gq -PLC-IP3 signalling was required for the CCK-8s-induced insulin secretion under low-glucose conditions, Gs -PKA/Epac signalling contributed more strongly to the CCK-8s-mediated insulin secretion in high-glucose conditions. CCK-8s also promoted formation of the CCK1 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
  Knowledge of different CCK1 receptor-activated downstream signalling pathways in the regulation of distinct functions of pancreatic beta cells could be used to identify biased CCK1 receptor ligands for the development of new anti-diabetic drugs.
authors.affiliation: Department of Biochemistry and Molecular Biology and Key Laboratory Experimental Teratology of the Ministry of Education, Jinan, Shandong, China.|Qilu Hospital, Shandong University, Jinan, Shandong, China.|Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Jinan, Shandong, China.
authors.forename: Shang-lei
authors.initials: SL
authors.lastname: Ning
authors.affiliation: Shandong Provincial School Key laboratory for Protein Science of Chronic degenerative diseases, Jinan, Shandong, China.|Department of Physiology, Shandong University School of Medicine, Jinan, Shandong, China.
authors.forename: Wen-shuai
authors.initials: WS
authors.lastname: Zheng
authors.affiliation: Shandong Provincial School Key laboratory for Protein Science of Chronic degenerative diseases, Jinan, Shandong, China.|Department of Physiology, Shandong University School of Medicine, Jinan, Shandong, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Su
authors.affiliation: Department of Biochemistry and Molecular Biology and Key Laboratory Experimental Teratology of the Ministry of Education, Jinan, Shandong, China.|Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Jinan, Shandong, China.
authors.forename: Nan
authors.initials: N
authors.lastname: Liang
authors.affiliation: Shandong Provincial School Key laboratory for Protein Science of Chronic degenerative diseases, Jinan, Shandong, China.|Department of Physiology, Shandong University School of Medicine, Jinan, Shandong, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Biochemistry and Molecular Biology and Key Laboratory Experimental Teratology of the Ministry of Education, Jinan, Shandong, China.|Shandong Provincial School Key laboratory for Protein Science of Chronic degenerative diseases, Jinan, Shandong, China.
authors.forename: Dao-lai
authors.initials: DL
authors.lastname: Zhang
authors.affiliation: Shandong Provincial School Key laboratory for Protein Science of Chronic degenerative diseases, Jinan, Shandong, China.|Department of Physiology, Shandong University School of Medicine, Jinan, Shandong, China.
authors.forename: Chun-hua
authors.initials: CH
authors.lastname: Liu
authors.affiliation: Department of Biochemistry and Molecular Biology and Key Laboratory Experimental Teratology of the Ministry of Education, Jinan, Shandong, China.|Department of Physiology, Shandong University School of Medicine, Jinan, Shandong, China.
authors.forename: Jun-hong
authors.initials: JH
authors.lastname: Dong
authors.affiliation: Department of Physiology, Shandong University School of Medicine, Jinan, Shandong, China.
authors.forename: Zheng-kui
authors.initials: ZK
authors.lastname: Zhang
authors.affiliation: Department of Physiology, Shandong University School of Medicine, Jinan, Shandong, China.
authors.forename: Min
authors.initials: M
authors.lastname: Cui
authors.affiliation: Department of Biochemistry and Molecular Biology and Key Laboratory Experimental Teratology of the Ministry of Education, Jinan, Shandong, China.|Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Jinan, Shandong, China.
authors.forename: Qiao-Xia
authors.initials: QX
authors.lastname: Hu
authors.affiliation: Shandong Provincial School Key laboratory for Protein Science of Chronic degenerative diseases, Jinan, Shandong, China.|Department of Physiology, Shandong University School of Medicine, Jinan, Shandong, China.
authors.forename: Chao-chao
authors.initials: CC
authors.lastname: Chen
authors.affiliation: Shandong Provincial Qianfoshan, Shandong University, Jinan, Shandong, China.
authors.forename: Chang-hong
authors.initials: CH
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, Hebei Medical University, Shijiazhuang, Hebei, China.
authors.forename: Chuan
authors.initials: C
authors.lastname: Wang
authors.affiliation: Shandong Provincial Hospital, Shandong University, Jinan, Shandong, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Pang
authors.affiliation: Qilu Hospital, Shandong University, Jinan, Shandong, China.
authors.forename: Yu-xin
authors.initials: YX
authors.lastname: Chen
authors.affiliation: Department of Biochemistry and Molecular Biology and Key Laboratory Experimental Teratology of the Ministry of Education, Jinan, Shandong, China.|Qilu Hospital, Shandong University, Jinan, Shandong, China.|Shandong Provincial School Key laboratory for Protein Science of Chronic degenerative diseases, Jinan, Shandong, China.|Department of Physiology, Shandong University School of Medicine, Jinan, Shandong, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Yu
authors.affiliation: Department of Biochemistry and Molecular Biology and Key Laboratory Experimental Teratology of the Ministry of Education, Jinan, Shandong, China.|Shandong Provincial School Key laboratory for Protein Science of Chronic degenerative diseases, Jinan, Shandong, China.|Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Jinan, Shandong, China.|Shandong Provincial Hospital, Shandong University, Jinan, Shandong, China.
authors.forename: Jin-peng
authors.initials: JP
authors.lastname: Sun
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D019390:Arrestins / Q000235:genetics; D002766:Cholecystokinin / Q000378:metabolism / Q000502:physiology*; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000166:cytology / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D011949:Receptors, Cholecystokinin / Q000378:metabolism*; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism; D015398:Signal Transduction; D000071559:beta-Arrestin 1; D000071557:beta-Arrestins
chemical_list: C000605255:Arrb1 protein, mouse; D019390:Arrestins; D007328:Insulin; D011949:Receptors, Cholecystokinin; D000071559:beta-Arrestin 1; D000071557:beta-Arrestins; D002766:Cholecystokinin; D038744:Ribosomal Protein S6 Kinases, 90-kDa