The Pharmacological Profile of Brain Liver Intestine Na+ Channel: Inhibition by Diarylamidines and Activation by Fenamates
The Pharmacological Profile of Brain Liver Intestine Na+ Channel: Inhibition by Diarylamidines and Activation by Fenamates
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DOI：
10.1124/mol.111.073726
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发表时间：
2011-11-01
影响因子：
3.6
通讯作者：
Gruender, Stefan
中科院分区：
文献类型：
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作者：
Wiemuth, Dominik;Gruender, Stefan
脑肝肠Na+通道（BLINaC）是功能未知的变性蛋白/上皮Na+通道基因家族的成员。BLINaC的生理功能的阐明将大大受益于特异性影响BLINaC活性的药理学工具。由BLINaC与酸敏感离子通道的密切分子关系的指导，我们在这项研究中发现，大鼠BLINaC（rBLINaC）和小鼠BLINaC被微摩尔浓度的二芳基脒和萘莫司他抑制，类似于酸敏感离子通道。抑制是电压依赖性的，这表明孔阻塞的抑制机制。此外，我们确定了芬那酯氟芬那酸和相关化合物作为rBLINaC的激动剂。应用毫摩尔浓度的氟芬那酸rBLINaC诱导一个强大的，Na+选择性电流，这是部分阻断阿米洛利。rBLINaC的人工激动剂的鉴定支持了rBLINaC被未知的生理配体打开的假设。二芳基脒的抑制和芬那酯的激活定义了BLINaC的独特药理学特征，这将有助于揭示该离子通道的生理功能。
The brain liver intestine Na+ channel (BLINaC) is a member of the degenerin/epithelial Na+ channel gene family of unknown function. Elucidation of the physiological function of BLINaC would benefit greatly from pharmacological tools that specifically affect BLINaC activity. Guided by the close molecular relation of BLINaC to acid-sensing ion channels, we discovered in this study that rat BLINaC (rBLINaC) and mouse BLINaC are inhibited by micromolar concentrations of diarylamidines and nafamostat, similar to acid-sensing ion channels. Inhibition was voltage-dependent, suggesting pore block as the mechanism of inhibition. Furthermore, we identified the fenamate flufenamic acid and related compounds as agonists of rBLINaC. Application of millimolar concentrations of flufenamic acid to rBLINaC induced a robust, Na+-selective current, which was blocked partially by amiloride. The identification of an artificial agonist of rBLINaC supports the hypothesis that rBLINaC is opened by an unknown physiological ligand. Inhibition by diarylamidines and activation by fenamates define a unique pharmacological profile for BLINaC, which will be useful to unravel the physiological function of this ion channel.