This proposal seeks to further define the cellular and subcellular processes that regulate calcium influx in airway smooth muscle. Previous studies have characterized receptor-activated calcium influx in human airway smooth muscle cells following exposure to bronchoconstrictive agents such as acetylcholine, histamine, and bradykinin. The focus of this proposal will be to more completely characterize the conductances associated with this calcium influx in an effort to determine the channel protein responsible for mediating sustained, agonist-induced contraction in airway smooth muscle, and to determine the molecular mechanisms by which calcium channel proteins are activated during this process. Single- cell, simultaneous measurements of calcium and current will be made using the nystatin modification of the whole-cell patch-clamp technique in order to directly examine the conductances that underlie sustained increases in cytosolic calcium during agonist exposure. Simultaneous measurements of force and cytosolic calcium in tissue strips will allow the correlation of single-cell and single-channel measurements with physiologic bronchoconstrictive responses. Mechanisms by which voltage-dependent calcium channels are modulated by agonist/receptor binding will also be examined, since this linkage is known to occur. These studies should provide specific information about the mechanisms by which exposure to bronchoconstrictive agents results in sustained increases in cytosolic calcium and attendant force production. Pharmacological regulation of these channel proteins may prove to be an efficient and specific method of bronchodilation.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL045239-08
Application #
2430695
Study Section
Lung Biology and Pathology Study Section (LBPA)
Project Start
1990-07-01
Project End
1998-05-31
Budget Start
1997-08-15
Budget End
1998-05-31
Support Year
8
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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