Arispe N, Ma J, Jacobson K A, Pollard H B
Institute for Molecular Medicine and Department of Anatomy and Cell Biology, Uniformed Services University School of Medicine (USUHS), Bethesda, Maryland 20814, USA.
J Biol Chem. 1998 Mar 6;273(10):5727-34. doi: 10.1074/jbc.273.10.5727.
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.
8-环戊基-1,3-二丙基黄嘌呤（CPX）和1,3-二烯丙基-8-环己基黄嘌呤（DAX）是黄嘌呤腺苷拮抗剂，可激活表达野生型或突变型（ΔF508）囊性纤维化跨膜传导调节因子（CFTR）的细胞中的氯离子外流。这些药物在极低浓度下就具有活性，表明它们在治疗囊性纤维化方面可能具有治疗用途。然而，目前尚不清楚这些化合物的作用机制。我们在此报告，激活细胞氯离子电流的相同低浓度CPX和DAX也能显著激活整合到平面脂质双分子层中的CFTR通道。激活过程涉及整合的CFTR通道总传导时间的显著增加。其机制包括通道开放事件的频率和持续时间增加。因此，这些药物在细胞中激活氯离子外流很可能涉及药物与CFTR蛋白的直接相互作用。我们预计，这一新信息将从根本上有助于合理开发这些及相关化合物用于囊性纤维化治疗。
