Mutations in the PKD2 gene cause autosomal-dominant polycystic kidney disease but the physiological role of polycystin-2, the protein product of PKD2, remains elusive. Polycystin-2 belongs to the transient receptor potential (TRP) family of non-selective cation channels. To test the hypothesis that altered ion channel properties of polycystin-2 compromise its putative role in a control circuit controlling lumen formation of renal tubular structures, we generated a mouse model in which we exchanged the pore loop of polycystin-2 with that of the closely related cation channel polycystin-2L1 (encoded by PKD2L1), thereby creating the protein polycystin-2poreL1. Functional characterization of this mutant channel in Xenopus laevis oocytes demonstrated that its electrophysiological properties differed from those of polycystin-2 and instead resembled the properties of polycystin-2L1, in particular regarding its permeability for Ca2+ ions. Homology modeling of the ion translocation pathway of polycystin-2poreL1 argues for a wider pore in polycystin-2poreL1 than in polycystin-2. In Pkd2poreL1 knock-in mice in which the endogenous polycystin-2 protein was replaced by polycystin-2poreL1 the diameter of collecting ducts was increased and collecting duct cysts developed in a strain-dependent fashion.

中文翻译：

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具有修饰通道特性的多囊蛋白 2 蛋白导致肾小管直径增加和肾囊肿。

PKD2 基因突变导致常染色体显性多囊肾病，但 PKD2 的蛋白质产物 polycystin-2 的生理作用仍然难以捉摸。Polycystin-2 属于非选择性阳离子通道的瞬时受体电位 (TRP) 家族。为了检验多囊蛋白 2 离子通道特性的改变会损害其在控制肾小管结构管腔形成的控制回路中的假定作用的假设，我们生成了一个小鼠模型，在该模型中，我们将多囊蛋白 2 的孔环与紧密连接的孔环交换。相关的阳离子通道 polycystin-2L1（由 PKD2L1 编码），从而产生蛋白质 polycystin-2poreL1。非洲爪蟾卵母细胞中这种突变通道的功能表征表明，其电生理特性不同于 polycystin-2，而是类似于 polycystin-2L1 的特性，特别是在其对 Ca2+ 离子的渗透性方面。polycystin-2poreL1 离子易位通路的同源模型表明，polycystin-2poreL1 中的孔比 polycystin-2 中的更宽。在 Pkd2poreL1 敲入小鼠中，内源性 polycystin-2 蛋白被 polycystin-2poreL1 取代，集合管的直径增加，集合管囊肿以应变依赖性方式发展。polycystin-2poreL1 离子易位通路的同源模型表明，polycystin-2poreL1 中的孔比 polycystin-2 中的更宽。在 Pkd2poreL1 敲入小鼠中，内源性 polycystin-2 蛋白被 polycystin-2poreL1 取代，集合管的直径增加，集合管囊肿以应变依赖性方式发展。polycystin-2poreL1 离子易位通路的同源模型表明，polycystin-2poreL1 中的孔比 polycystin-2 中的更宽。在 Pkd2poreL1 敲入小鼠中，内源性 polycystin-2 蛋白被 polycystin-2poreL1 取代，集合管的直径增加，集合管囊肿以应变依赖性方式发展。