Intracellular Ca 2+ signaling and the regulation of vesicular exocytosis are two fundamental physiological properties of all eukaryotic cells. They have been analyzed in detail in only a few exemplar cell types. We need precise descriptions in each cell type to understand the implications for disease and therapy. This project will study pancreatic beta-cells, pancreatic ductal epithelium, chromaffin cells, pituitary gonadotropes, and sympathetic neurons. It will use patch clamp biophysical methods and optical Ca 2+ reporters to quantitate sources and sinks of Ca 2+ in differentiated mammalian endocrine, nerve, and epithelial cells. One focus will be on Ca 2+ buffering and Ca 2+ clearance. In these cells, cytoplasmic buffering and four membrane clearance processes shape the Ca 2+ transient and thus regulate secretion of the endocrine hormones insulin, adrenaline, and gonadotropins and the secretion of mucus of the gastrointestinal tract. Defects in regulation of secretion underlie some forms of diabetes, infertility, cystic fibrosis, and digestive disorders. We need basic understanding to inspire new therapeutic approaches. This project will determine a kinetic model for the secretory vesicle pools of pancreatic ductal epithelium, including their regulation by Ca 2+, protein kinases, and other physiological variables. The Ca 2+ buffering and Ca 2+ clearance mechanisms of sympathetic neurons, pancreatic beta-cells, and pancreatic ductal epithelial cells will be dissected and described by a quantitative model. Our analysis of the Ca 2+ dynamics within the endoplasmic reticulum of gonadotropes and within the mitochondria of chromaffin cells will be deepened. What are the Ca 2+ buffering and flux properties of these organelles? Our work in these cells concerns processes whose failure leads to disease and whose modulation offers new therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR017803-32
Application #
7215636
Study Section
Molecular, Cellular and Developmental Neurosciences 2 (MDCN)
Program Officer
Boyce, Amanda T
Project Start
1977-09-01
Project End
2008-03-31
Budget Start
2007-04-01
Budget End
2008-03-31
Support Year
32
Fiscal Year
2007
Total Cost
$248,679
Indirect Cost
Name
University of Washington
Department
Physiology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
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Cho, Jung-Hwa; Chen, Liangyi; Kim, Mean-Hwan et al. (2010) Characteristics and functions of {alpha}-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptors expressed in mouse pancreatic {alpha}-cells. Endocrinology 151:1541-50
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Suh, Byung-Chang; Inoue, Takanari; Meyer, Tobias et al. (2006) Rapid chemically induced changes of PtdIns(4,5)P2 gate KCNQ ion channels. Science 314:1454-7
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Jung, Seung-Ryoung; Kim, Kyungjin; Hille, Bertil et al. (2006) Pattern of Ca2+ increase determines the type of secretory mechanism activated in dog pancreatic duct epithelial cells. J Physiol 576:163-78
Horowitz, Lisa F; Hirdes, Wiebke; Suh, Byung-Chang et al. (2005) Phospholipase C in living cells: activation, inhibition, Ca2+ requirement, and regulation of M current. J Gen Physiol 126:243-62

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