The stomach acts as the primary site of digestion of food taken into the body. The ability of the stomach to digest this food is linked to having sufficient substrates for controlled acid secretion, and functional transport proteins at the apical and basolateral membrane of the gastric gland along with sufficient bicarbonate containing mucus at the surface of the stomach to prevent erosion of the membranes due to the released acid. The regulated release of ions is normally controlled by neuronal and hormonal regulatory pathways. However, the exact mechanisms of controlled acid release are not known, as well as a complete characterization of the transport proteins that line the basolateral and apical membranes. The recent discovery of a divalent cation receptor on the basolateral membrane of the gastric gland as well as the identification of an apical Na-H transport protein and a surface cell NBC protein complex have added addition insights into the regulation of acid secretion. The ability to use an intact surface preparation, in combination with the isolated perfused single gastric gland gives important vehicles for studying and modeling the intact tissues. The regulation of these transporters and the transfer of signal information from one cell to the other is of great importance in understanding the complex issues of acid secretion in health and disease. To add to the investigative arsenal we have recently developed transgenic models that will allow direct manipulation of the secretory and regulatory pathways associated with acid secretion in the stomach. The goal of the present application is to classify, and characterize the apical and basolateral membrane associated acid-base transporters and to determine what role the newly identified divalent cation receptor plays in controlling their activity. Special emphasis will be given to the newly identified apical Na-H, and the basolateral Na/HCO3 in the gland and surface cell preparations. Additional studies will also address the role of gap junctions in regulated acid secretion. These studies will include the use of isolated perfused gastric glands, surface cells, and transgenic models to study in detail the importance of the proteins which control acid secretion. The characterization and modulation of transport proteins and receptors will enhance our basic understanding of regulated acid secretion and will play an important role in developing new strategies for the treatment of gastric related illness in the population.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK050230-07
Application #
6607401
Study Section
Surgery and Bioengineering Study Section (SB)
Program Officer
May, Michael K
Project Start
1997-02-01
Project End
2005-04-30
Budget Start
2003-07-01
Budget End
2004-04-30
Support Year
7
Fiscal Year
2003
Total Cost
$408,750
Indirect Cost
Name
Yale University
Department
Surgery
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Vucic, Esad; Alfadda, Tariq; MacGregor, Gordon G et al. (2015) Kir1.1 (ROMK) and Kv7.1 (KCNQ1/KvLQT1) are essential for normal gastric acid secretion: importance of functional Kir1.1. Pflugers Arch 467:1457-1468
Sidani, Shafik; Kopic, Sascha; Socrates, Thenral et al. (2009) AMP-activated protein kinase: a physiological off switch for murine gastric acid secretion. Pflugers Arch 459:39-46
Kosiek, Ortrud; Busque, Stephanie M; Foller, Michael et al. (2007) SLC26A7 can function as a chloride-loading mechanism in parietal cells. Pflugers Arch 454:989-98
Remy, Christine; Kirchhoff, Philipp; Hafner, Patricia et al. (2007) Stimulatory pathways of the Calcium-sensing receptor on acid secretion in freshly isolated human gastric glands. Cell Physiol Biochem 19:33-42
Sidani, Shafik M; Kirchhoff, Philipp; Socrates, Thenral et al. (2007) DeltaF508 mutation results in impaired gastric acid secretion. J Biol Chem 282:6068-74
Ghosh, Sikha; Choritz, Lars; Geibel, John et al. (2006) Somatostatin modulates PI3K-Akt, eNOS and NHE activity in the ciliary epithelium. Mol Cell Endocrinol 253:63-75
Kirchhoff, Philipp; Dave, Mital H; Remy, Christine et al. (2006) An amino acid transporter involved in gastric acid secretion. Pflugers Arch 451:738-48
Roepke, Torsten K; Anantharam, Arun; Kirchhoff, Philipp et al. (2006) The KCNE2 potassium channel ancillary subunit is essential for gastric acid secretion. J Biol Chem 281:23740-7
Eisenberg, Michael L; Maker, Ajay V; Slezak, Lori A et al. (2005) Insulin receptor (IR) and glucose transporter 2 (GLUT2) proteins form a complex on the rat hepatocyte membrane. Cell Physiol Biochem 15:51-8
Hoffman, Joseph F; Geibel, John P (2005) Fluorescent imaging of Cl- in Amphiuma red blood cells: how the nuclear exclusion of Cl- affects the plasma membrane potential. Proc Natl Acad Sci U S A 102:921-6

Showing the most recent 10 out of 32 publications