Abstract

This is a proposal to examine the physiological role of cholecystokinin (CCK)-58, the main circulating form of CCK. The applicant and his coworkers have succeeded recently in synthesizing canine and rat CCK-58 and have found that rat CCK-58 is substantially more potent than CCK-8 for stimulation of pancreatic enzyme and fluid secretion in rats. NMR analysis shows that CCK-58 has a different solution conformation than CCK-8 and that the conformation is stable enough to allow CCK-58 to bind more potently to CCK-A receptors on pancreatic acinar cells. Based on these results, the PI has formulated a hypothesis whereby processing of CCK-58 to CCK-8 changes the conformation of the active carboxyl terminus, which in turn modifies the intracellular signals and results in altered bioactivity. The following studies are proposed to test this hypothesis: (1) establish an assay capable of detecting functional differences in the conformation of the carboxyl terminus of CCK-58; (2) demonstrate that the conformation of the carboxyl terminus of CCK-58 is stabilized by interactions between this and other regions of CCK-58; and (3) examine how the stable conformation of the carboxyl terminus of CCK-58 alters the expression of its bioactivity.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK033850-10
Application #
2734026
Study Section
Special Emphasis Panel (ZRG2-MET (01))
Program Officer
May, Michael K
Project Start
1984-04-01
Project End
2002-06-30
Budget Start
1998-07-01
Budget End
1999-06-30
Support Year
10
Fiscal Year
1998
Total Cost
Indirect Cost

  Institution

Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
119132785
City
Los Angeles
State
CA
Country
United States
Zip Code
90095

  Publications

Overduin, Joost; Gibbs, James; Cummings, David E et al. (2014) CCK-58 elicits both satiety and satiation in rats while CCK-8 elicits only satiation. Peptides 54:71-80
Goebel-Stengel, Miriam; Stengel, Andreas; Taché, Yvette et al. (2011) The importance of using the optimal plasticware and glassware in studies involving peptides. Anal Biochem 414:38-46
Keire, David A; Whitelegge, Julian P; Souda, Puneet et al. (2010) PYY(1-36) is the major form of PYY in rat distal small intestine: quantification using high-resolution mass spectrometry. Regul Pept 165:151-7
Thrower, Edwin C; Wang, Jeffrey; Cheriyan, Salim et al. (2009) Protein kinase C delta-mediated processes in cholecystokinin-8-stimulated pancreatic acini. Pancreas 38:930-5
Criddle, David N; Booth, David M; Mukherjee, Rajarshi et al. (2009) Cholecystokinin-58 and cholecystokinin-8 exhibit similar actions on calcium signaling, zymogen secretion, and cell fate in murine pancreatic acinar cells. Am J Physiol Gastrointest Liver Physiol 297:G1085-92
Stengel, Andreas; Keire, David; Goebel, Miriam et al. (2009) The RAPID method for blood processing yields new insight in plasma concentrations and molecular forms of circulating gut peptides. Endocrinology 150:5113-8
Murphy, John A; Criddle, David N; Sherwood, Mark et al. (2008) Direct activation of cytosolic Ca2+ signaling and enzyme secretion by cholecystokinin in human pancreatic acinar cells. Gastroenterology 135:632-41
Kumar, Mohanraja; Reeve Jr, Joseph R; Hu, Weidong et al. (2008) The micelle-associated 3D structures of Boc-Y(SO3)-Nle-G-W-Nle-D-2-phenylethylester (JMV-180) and CCK-8(s) share conformational elements of a calculated CCK1 receptor-bound model. J Med Chem 51:3742-54
Keire, David A; Whitelegge, Julian P; Bassilian, Sara et al. (2008) A new endogenous form of PYY isolated from canine ileum: Gly-extended PYY(1-36). Regul Pept 151:61-70
Cooper, Marvis S; Reeve Jr, Joseph R; Abdalla, Mohamed O et al. (2008) Cholecystokinin-33 is more effective than cholecystokinin-8 in inhibiting food intake and in stimulating the myenteric plexus and dorsal vagal complex. Brain Res 1205:27-35

Showing the most recent 10 out of 47 publications