Contraction of airway smooth muscle cause airway obstruction, and relaxation of this muscle is the principal action of B-adrenergic agonists used to treat asthma. Calcium, both extracellular and that released from intracellular stores, is an important second messenger that contributes to the determination of tension in smooth muscle. However, a paradox underscores our limited understanding of how cytosolic calcium concentrations ([Ca2+])i are regulated in airway smooth muscle cells. First, studies have shown that B-adrenergic agonists and muscarinic agonists both stimulated calcium influx and caused large increases in basal [Ca2+]i, yet paradoxically, had different effects on tension. To explain this, it is hypothesized that the cytosol is not homogeneous with respect to calcium concentrations. Independent of regulating the net flux of calcium that determines tension, muscarinic and B-adrenergic agonists stimulate calcium influx pathways that are either functionally or anatomically segregated at the periphery of the cell. These segregated influx pathways maintain peripheral sarcoplasmic reticulum (SR) calcium stores but are not major determinants of tension. Progress supports this general hypothesis and, further, it appears that SR refilling may have unique features in airway smooth muscle. Since SR calcium stores are important for understanding smooth muscle responses to multiple stimulations by contractile agonists as probably occurs in asthma, th aims of continuing this study are to better understand SR refilling.
The aims are: (1) in the absence of agonist, determine how the sarcoplasmic reticulum (SR) refills after being depleted of calcium; (2) determine whether protein tyrosine kinases and the cytoskeleton support SR refilling: (3) characterize S refilling during sustained muscarinic stimulation; (4) characterize SR refilling in the presence of B-adrenergic agonists. To address these aims, the principal method is radiometric imaging of [Ca2+]i in single, bovine airway smooth muscle cells loaded with the calcium dye, fura-2.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL054143-05
Application #
2883264
Study Section
Lung Biology and Pathology Study Section (LBPA)
Project Start
1995-04-01
Project End
2001-02-28
Budget Start
1999-03-01
Budget End
2000-02-29
Support Year
5
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
660735098
City
Worcester
State
MA
Country
United States
Zip Code
01655
Martin, Gilles; O'Connell, Robert J; Pietrzykowski, Andrzej Z et al. (2008) Interleukin-4 activates large-conductance, calcium-activated potassium (BKCa) channels in human airway smooth muscle cells. Exp Physiol 93:908-18
Ethier, Michael F; Madison, J Mark (2006) Adenosine A1 receptors mediate mobilization of calcium in human bronchial smooth muscle cells. Am J Respir Cell Mol Biol 35:496-502
Ethier, Michael F; Madison, J Mark (2006) IL-4 inhibits calcium transients in bovine trachealis cells by a ryanodine receptor-dependent mechanism. FASEB J 20:154-6
Ethier, Michael F; Cappelluti, Erika; Madison, J Mark (2005) Mechanisms of interleukin-4 effects on calcium signaling in airway smooth muscle cells. J Pharmacol Exp Ther 313:127-33
Madison, J Mark (2003) Migration of airway smooth muscle cells. Am J Respir Cell Mol Biol 29:8-11
Ethier, M F; Madison, J M (2002) LY294002, but not wortmannin, increases intracellular calcium and inhibits calcium transients in bovine and human airway smooth muscle cells. Cell Calcium 32:31-8
Ethier, M F; Yamaguchi, H; Madison, J M (2001) Effects of cyclopiazonic acid on cytosolic calcium in bovine airway smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 281:L126-33
Madison, J M; Ethier, M F (2001) Interleukin-4 rapidly inhibits calcium transients in response to carbachol in bovine airway smooth muscle cells. Am J Respir Cell Mol Biol 25:239-44
Ethier, M F; Dextradeur, T; Schaefer, O P et al. (2000) Effects of salmeterol on muscarinic inhibition of adenylyl cyclase in bovine trachealis cells. Life Sci 67:2753-8
Madison, J M; Ethier, M F; Yamaguchi, H (1998) Refilling of caffeine-sensitive intracellular calcium stores in bovine airway smooth muscle cells. Am J Physiol 275:L852-60

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