Martí-Solans Josep, Børve Aina, Hejnol Andreas, Lynagh Timothy
Michael Sars Centre, University of Bergen, Bergen, Norway.
Department of Biological Sciences, University of Bergen, Bergen, Norway.
J Biol Chem. 2025 Jan;301(1):108066. doi: 10.1016/j.jbc.2024.108066. Epub 2024 Dec 10.
Diarylamidines are a group of widely used small molecule drugs. One common use of diarylamidines is their pharmacological inhibition of ligand-gated cation channels, including tetrameric ionotropic glutamate receptors and trimeric degenerin/epithelial sodium channel/acid-sensing ion channels. Here, we discover a degenerin/epithelial sodium channel/acid-sensing ion channel from the brachiopod (lamp shell) Novocrania anomala, at which diarylamidines act as agonists. The channel is closely related to bile acid-gated, pH-gated, and peptide-gated channels but is not activated by such stimuli. We describe activation of the channel by diminazene, 4',6-diamidino-2-phenylindole, and pentamidine, examine several biophysical and pharmacological properties, and briefly explore the molecular determinants of channel activity with site-directed mutagenesis. We term this channel the diarylamidine-activated sodium channel.
双脒基化合物是一类广泛使用的小分子药物。双脒基化合物的一个常见用途是其对配体门控阳离子通道的药理学抑制作用，包括四聚体离子型谷氨酸受体和三聚体退化蛋白/上皮钠通道/酸敏感离子通道。在此，我们从腕足动物（灯贝）异常新碟贝中发现了一种退化蛋白/上皮钠通道/酸敏感离子通道，双脒基化合物在此通道上作为激动剂起作用。该通道与胆汁酸门控、pH门控和肽门控通道密切相关，但不受此类刺激激活。我们描述了双脒苯脲、4',6-二脒基-2-苯基吲哚和喷他脒对该通道的激活作用，研究了其几种生物物理和药理学特性，并通过定点诱变简要探索了通道活性的分子决定因素。我们将此通道命名为双脒基激活钠通道。
