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J Biol Chem, Vol. 273, Issue 10, 5727-5734, March 6, 1998
,
From the 8-Cyclopentyl-1,3-dipropylxanthine (CPX) and
1,3-diallyl-8-cyclohexylxanthine (DAX) are xanthine adenosine
antagonists which activate chloride efflux from cells expressing either
wild-type or mutant ( Institute for Molecular Medicine and
Department of Anatomy and Cell Biology, Uniformed Services University
School of Medicine (USUHS), Bethesda, Maryland 20814, the
§ Department of Physiology and Biophysics, Case-Western
Reserve University, Cleveland, Ohio 44106, and the ¶ Section on
Bioorganic Chemistry, Laboratory of Chemistry, NIDDK, National
Institutes of Health, Bethesda, Maryland 20892
F508) cystic fibrosis transmembrane conductance
regulator (CFTR). These drugs are active in extremely low
concentrations, suggesting their possible therapeutic uses in treating
cystic fibrosis. However, knowledge of the mechanism of action of these compounds is lacking. We report here that the same low concentrations of both CPX and DAX which activate chloride currents from cells also
generate a profound activation of CFTR channels incorporated into
planar lipid bilayers. The process of activation involves a pronounced
increase in the total conductive time of the incorporated CFTR
channels. The mechanism involves an increase in the frequency and
duration of channel opening events. Thus, activation by these drugs of
chloride efflux in cells very likely involves direct interaction of the
drugs with the CFTR protein. We anticipate that this new information
will contribute fundamentally to the rational development of these and
related compounds for cystic fibrosis therapy.
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