Mutations of PKD2, which encodes polycystin-2, cause autosomal dominant polycystic kidney disease (ADPKD). The prevailing view is that defects in polycystin-2–mediated calcium ion influx in the primary cilia play a central role in the pathogenesis of cyst growth. However, polycystin-2 is predominantly expressed in the endoplasmic reticulum (ER) and more permeable to potassium ions than to calcium ions.

The trimeric intracellular cation (TRIC) channel TRIC-B is an ER-resident potassium channel that mediates potassium–calcium counterion exchange for inositol trisphosphate–mediated calcium ion release. Using TRIC-B as a tool, we examined the function of ER-localized polycystin-2 and its role in ADPKD pathogenesis in cultured cells, zebrafish, and mouse models.

Agonist-induced ER calcium ion release was defective in cells lacking polycystin-2 and reversed by exogenous expression of TRIC-B. Vice versa, exogenous polycystin-2 reversed an ER calcium-release defect in cells lacking TRIC-B. In a zebrafish model, expression of wild-type but not nonfunctional TRIC-B suppressed polycystin-2–deficient phenotypes. Similarly, these phenotypes were suppressed by targeting the ROMK potassium channel (normally expressed on the cell surface) to the ER. In cultured cells and polycystin-2–deficient zebrafish phenotypes, polycystin-2 remained capable of reversing the ER calcium release defect even when it was not present in the cilia. Transgenic expression of Tric-b ameliorated cystogenesis in the kidneys of conditional Pkd2-inactivated mice, whereas Tric-b deletion enhanced cystogenesis in Pkd2-heterozygous kidneys.

Polycystin-2 in the ER appears to be critical for anticystogenesis and likely functions as a potassium ion channel to facilitate potassium–calcium counterion exchange for inositol trisphosphate–mediated calcium release. The results advance the understanding of ADPKD pathogenesis and provides proof of principle for pharmacotherapy by TRIC-B activators.

编码多囊蛋白-2的PKD2突变会导致常染色体显性多囊肾病 (ADPKD)。普遍的观点是，初级纤毛中多囊蛋白-2 介导的钙离子流入缺陷在囊肿生长的发病机制中发挥着核心作用。然而，多囊蛋白-2 主要在内质网 (ER) 中表达，并且对钾离子的渗透性比对钙离子的渗透性更高。

三聚体细胞内阳离子 (TRIC) 通道 TRIC-B 是一种内质网驻留钾通道，可介导钾-钙抗衡离子交换，从而促进肌醇三磷酸介导的钙离子释放。使用 TRIC-B 作为工具，我们在培养细胞、斑马鱼和小鼠模型中检查了 ER 定位的多囊蛋白-2 的功能及其在 ADPKD 发病机制中的作用。

缺乏多囊蛋白-2 的细胞中激动剂诱导的 ER 钙离子释放存在缺陷，并可通过 TRIC-B 的外源表达逆转。反之亦然，外源性多囊蛋白-2 逆转了缺乏 TRIC-B 的细胞中的 ER 钙释放缺陷。在斑马鱼模型中，野生型但非功能性 TRIC-B 的表达抑制了多囊蛋白 2 缺陷表型。同样，这些表型通过将 ROMK 钾通道（通常在细胞表面表达）靶向内质网而受到抑制。在培养细胞和缺乏多囊蛋白 2 的斑马鱼表型中，多囊蛋白 2 仍然能够逆转内质网钙释放缺陷，即使它不存在于纤毛中。Tric-b的转基因表达改善了条件性Pkd2失活小鼠肾脏中的囊肿发生，而Tric-b缺失则增强了Pkd2杂合子肾脏中的囊肿发生。

内质网中的多囊蛋白-2 似乎对于抗膀胱生成至关重要，并且可能充当钾离子通道，促进钾-钙抗衡离子交换，从而促进肌醇三磷酸介导的钙释放。这些结果增进了对 ADPKD 发病机制的理解，并为 TRIC-B 激活剂的药物治疗提供了原理证明。