Ingested nutrients stimulate secretion of gastrointestinal hormones that are necessary for the coordinated processes of digestion and absorption of food. One of the most important hormonal regulators of the digestive process is cholecystokinin (CCK)). This hormone is concentrated in the proximal small intestine and is secreted into the blood upon the ingestion of proteins and fats. The physiologic actions of CCK include stimulation of pancreatic secretion and gallbladder contraction, regulation of gastric emptying, and induction of satiety. Therefore, in a highly coordinated manner CCK regulates the ingestion, digestion, and absorption of nutrients. The manner by which foods affect enteric hormone secretion is largely unknown. However, it has recently become apparent two """"""""CCK releasing factors"""""""" are present in the lumen of the proximal small intestine. One of these factors, known as monitor peptide, has been chemically characterized. Monitor peptide is produced by pancreatic acinar cells and is secreted by way of the pancreatic duct into the duodenum. Upon reaching the small intestine monitor peptide interacts with CCK cells to induce hormone secretion. Studies in the PI's laboratory have demonstrated that monitor peptide directly stimulates CCK release from isolated intestinal mucosal cells and from an intestinal CCK-containing cell line. Moreover, monitor peptide has been used to enrich CCK-containing cells by calcium fluorescence-activated cell sorting. The observations that monitor peptide stimulates CCK release in a calcium- dependent manner and recent radioligand binding data have lead to the hypothesis that luminal releasing factors, such as monitor peptide, affect CCK secretion through a receptor-mediated mechanism. The objective of these studies is to evaluate the manner by which luminal releasing factors (with monitor peptide as the prototype) activate the intracellular signaling pathways that lead to CCK secretion. Preliminary studies have identified several heterotrimeric GTP-binding (g) proteins present in CCK cells which are proposed to participate in monitor peptide-stimulated CCK secretion. Therefore, the first Specific Aim of these studies is to: (1) characterize the heterotrimeric GTP binding proteins (G proteins) and t heir receptor coupling in CCK-producing cells. The second Specific Aim will be to (2) determine the second messenger pathways involved in monitor peptide-stimulated CCK release with particular emphasis on modulation of adenylyl cyclase, phospholipase C, and regulation of CCK release by protein phosphatases. The final Specific Aim will be to (3) clone the cDNA encoding the monitor peptide receptor in order to more fully understand the molecular interactions involved with receptor-stimulated signaling by luminal releasing factors.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
General Medicine A Subcommittee 2 (GMA)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Duke University
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Bohórquez, Diego V; Liddle, Rodger A (2011) Axon-like basal processes in enteroendocrine cells: characteristics and potential targets. Clin Transl Sci 4:387-91
Chandra, Rashmi; Liddle, Rodger A (2011) Recent advances in pancreatic endocrine and exocrine secretion. Curr Opin Gastroenterol 27:439-43
Bohórquez, Diego V; Chandra, Rashmi; Samsa, Leigh Ann et al. (2011) Characterization of basal pseudopod-like processes in ileal and colonic PYY cells. J Mol Histol 42:3-13
Wang, Yu; Chandra, Rashmi; Samsa, Leigh Ann et al. (2011) Amino acids stimulate cholecystokinin release through the Ca2+-sensing receptor. Am J Physiol Gastrointest Liver Physiol 300:G528-37
Nathan, Jaimie D; Romac, Joelle; Peng, Ruth Y et al. (2010) Protection against chronic pancreatitis and pancreatic fibrosis in mice overexpressing pancreatic secretory trypsin inhibitor. Pancreas 39:e24-30
Romac, Joelle M-J; Ohmuraya, Masaki; Bittner, Cathy et al. (2010) Transgenic expression of pancreatic secretory trypsin inhibitor-1 rescues SPINK3-deficient mice and restores a normal pancreatic phenotype. Am J Physiol Gastrointest Liver Physiol 298:G518-24
Chandra, Rashmi; Liddle, Rodger A (2009) Neural and hormonal regulation of pancreatic secretion. Curr Opin Gastroenterol 25:441-6
Chandra, Rashmi; Liddle, Rodger A (2007) Cholecystokinin. Curr Opin Endocrinol Diabetes Obes 14:63-7
Liddle, Rodger A (2006) Pathophysiology of SPINK mutations in pancreatic development and disease. Endocrinol Metab Clin North Am 35:345-56, x
Reeve Jr, Joseph R; Liddle, Rodger A; Shively, John E et al. (2006) Sequence variation outside the ""active"" region of dog and rabbit cholecystokinin-58 results in bioactivity differences. Pancreas 32:306-13

Showing the most recent 10 out of 77 publications