title: Direct activation of cystic fibrosis transmembrane conductance regulator channels by 8-cyclopentyl-1,3-dipropylxanthine (CPX) and 1,3-diallyl-8-cyclohexylxanthine (DAX).
abstract: 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 (DeltaF508) 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.
authors.affiliation: Institute for Molecular Medicine and Department of Anatomy and Cell Biology, Uniformed Services University School of Medicine (USUHS), Bethesda, Maryland 20814, USA.
authors.forename: N
authors.initials: N
authors.lastname: Arispe
authors.forename: J
authors.initials: J
authors.lastname: Ma
authors.forename: K A
authors.initials: KA
authors.lastname: Jacobson
authors.forename: H B
authors.initials: HB
authors.lastname: Pollard
mesh_terms: D002460:Cell Line; D018118:Chloride Channels / Q000187:drug effects; D003550:Cystic Fibrosis / Q000188:drug therapy; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism*; D004553:Electric Conductivity; D004594:Electrophysiology; D006801:Humans; D008051:Lipid Bilayers / Q000378:metabolism; D011189:Potassium Chloride / Q000378:metabolism; D058915:Purinergic P1 Receptor Antagonists; D014970:Xanthines / Q000494:pharmacology*
chemical_list: C111177:1,3-diallyl-8-cyclohexylxanthine; C505032:CFTR protein, human; D018118:Chloride Channels; D008051:Lipid Bilayers; D058915:Purinergic P1 Receptor Antagonists; D014970:Xanthines; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D011189:Potassium Chloride; C051360:1,3-dipropyl-8-cyclopentylxanthine