The overall objective of this proposal is to understand the cellular mechanisms of airway epithelia ion transport. Airway epithelia secrete chloride to regulate the quantity and composition of the respiratory tract fluid, an important component of pulmonary mucociliary clearance. The main emphasis of this work is on the regulation of the ion channels in tracheal epithelia and in understanding the mechanism of ion permeation through the membrane channels.
The specific aims of the proposal are; first, to understand the regulation of the apical membrane chloride channel. Specific emphasis will be on the role of cyclic AMP-dependent protein kinase, calcium, protein kinase C, and pH in regulation of the channel. The second main goal is focused on the basolateral membrane potassium channel. Preliminary studies indicate that the channel is regulated by calcium, however, an understanding of its regulation requires quantitation of the effect and examination of the possibility that other agents may interact with calcium to regulate overall channel activity. Because calcium regulates the channel, it will also be important to directly measure intracellular-free calcium concentrations in airway epithelial cells. To address these specific aims, cellular electrophysiologic techniques, including the patch-clamp technique, and optical techniques designed to measure intracelllar calcium will be used. The knowledge obtained in these studies may be of particular importance of our understanding the mechanism and regulation of chloride secretion under normal conditions and in diseases, such as cystic fibrosis. Cystic fibrosis is a disease characterized by a chloride impermeability in multiple epithelia.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL029851-07
Application #
3340923
Study Section
Physiology Study Section (PHY)
Project Start
1986-07-01
Project End
1991-06-30
Budget Start
1989-07-01
Budget End
1990-06-30
Support Year
7
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of Iowa
Department
Type
Schools of Medicine
DUNS #
041294109
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Randak, Christoph O; Welsh, Michael J (2005) ADP inhibits function of the ABC transporter cystic fibrosis transmembrane conductance regulator via its adenylate kinase activity. Proc Natl Acad Sci U S A 102:2216-20
Randak, Christoph O; Welsh, Michael J (2005) Adenylate kinase activity in ABC transporters. J Biol Chem 280:34385-8
Berger, Allan L; Randak, Christoph O; Ostedgaard, Lynda S et al. (2005) Curcumin stimulates cystic fibrosis transmembrane conductance regulator Cl- channel activity. J Biol Chem 280:5221-6
Berger, Allan L; Ikuma, Mutsuhiro; Welsh, Michael J (2005) Normal gating of CFTR requires ATP binding to both nucleotide-binding domains and hydrolysis at the second nucleotide-binding domain. Proc Natl Acad Sci U S A 102:455-60
Randak, Christoph; Welsh, Michael J (2003) An intrinsic adenylate kinase activity regulates gating of the ABC transporter CFTR. Cell 115:837-50
Liu, Lei; Leonard, A Soren; Motto, David G et al. (2003) Contribution of Drosophila DEG/ENaC genes to salt taste. Neuron 39:133-46
Berger, Allan L; Ikuma, Mutsuhiro; Hunt, John F et al. (2002) Mutations that change the position of the putative gamma-phosphate linker in the nucleotide binding domains of CFTR alter channel gating. J Biol Chem 277:2125-31
Hennager, D J; Ikuma, M; Hoshi, T et al. (2001) A conditional probability analysis of cystic fibrosis transmembrane conductance regulator gating indicates that ATP has multiple effects during the gating cycle. Proc Natl Acad Sci U S A 98:3594-9
Cotten, J F; Welsh, M J (1999) Cystic fibrosis-associated mutations at arginine 347 alter the pore architecture of CFTR. Evidence for disruption of a salt bridge. J Biol Chem 274:5429-35
Hall, R A; Ostedgaard, L S; Premont, R T et al. (1998) A C-terminal motif found in the beta2-adrenergic receptor, P2Y1 receptor and cystic fibrosis transmembrane conductance regulator determines binding to the Na+/H+ exchanger regulatory factor family of PDZ proteins. Proc Natl Acad Sci U S A 95:8496-501

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