The central goal of this project is to characterize the mechanisms of regulation of the four cellular transport processes involved in net Cl movement across secretory epithelia. At the basolateral membrane, these include NaCl co-transport mechanisms, Na/K pumps, and K channels; and, at the apical membrane, Cl channels. The effects of cAMP- and Ca-dependent agonists will be evaluated by monitoring ionic currents and transepithelial fluxes across polyene-treated tissues and by application of conventional and ion-selective microelectrode and patch clamp techniques to isolated tracheal epithelium, primary tracheal cell cultures and colonic tumor cell cultures. The effects of cAMP- and Ca-dependent intracellular regulatory systems (e.g. protein kinases) on Cl and K conductances and channel kinetics will also be examined. Secretagogue-induced cell volume alterations and the role of volume regulation in the concerted response to secretory agonists will be determined. Finally, we will evaluate the cellular basis for dual regulation of NaCl co-transport and K conductance in two absorptive epithelia whose transport processes resemble those found in secretory tissues. Our studies will provide a complete characterization of the mechanisms underlyng cAMP- and Ca-dependent regulation and permit construction of a dynamic model of the events involved in stimulation of Cl-secreting epthelia.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK031091-09
Application #
3229852
Study Section
General Medicine B Study Section (GMB)
Project Start
1981-09-01
Project End
1990-08-31
Budget Start
1989-09-01
Budget End
1990-08-31
Support Year
9
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Type
School of Medicine & Dentistry
DUNS #
004514360
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Devor, D C; Frizzell, R A (1998) Modulation of K+ channels by arachidonic acid in T84 cells. I. Inhibition of the Ca(2+)-dependent K+ channel. Am J Physiol 274:C138-48
Devor, D C; Frizzell, R A (1998) Modulation of K+ channels by arachidonic acid in T84 cells. II. Activation of a Ca(2+)-independent K+ channel. Am J Physiol 274:C149-60
Devor, D C; Singh, A K; Gerlach, A C et al. (1997) Inhibition of intestinal Cl- secretion by clotrimazole: direct effect on basolateral membrane K+ channels. Am J Physiol 273:C531-40
Devor, D C; Singh, A K; Bridges, R J et al. (1997) Psoralens: novel modulators of Cl- secretion. Am J Physiol 272:C976-88
Devor, D C; Singh, A K; Bridges, R J et al. (1996) Modulation of Cl- secretion by benzimidazolones. II. Coordinate regulation of apical GCl and basolateral GK. Am J Physiol 271:L785-95
Devor, D C; Singh, A K; Frizzell, R A et al. (1996) Modulation of Cl- secretion by benzimidazolones. I. Direct activation of a Ca(2+)-dependent K+ channel. Am J Physiol 271:L775-84
Rechkemmer, G; Frizzell, R A; Halm, D R (1996) Active potassium transport across guinea-pig distal colon: action of secretagogues. J Physiol 493 ( Pt 2):485-502
Frizzell, R A (1995) Functions of the cystic fibrosis transmembrane conductance regulator protein. Am J Respir Crit Care Med 151:S54-8
Halm, D R; Halm, S T; DiBona, D R et al. (1995) Selective stimulation of epithelial cells in colonic crypts: relation to active chloride secretion. Am J Physiol 269:C929-42
Devor, D C; Forrest Jr, J N; Suggs, W K et al. (1995) cAMP-activated Cl- channels in primary cultures of spiny dogfish (Squalus acanthias) rectal gland. Am J Physiol 268:C70-9

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