Department of Physiology, University of California San Francisco, San Francisco, CA, USA.
Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA.
Nat Commun. 2024 Jul 31;15(1):6468. doi: 10.1038/s41467-024-50318-9.
Polycystin-1 (PC-1) and PC-2 form a heteromeric ion channel complex that is abundantly expressed in primary cilia of renal epithelial cells. This complex functions as a non-selective cation channel, and mutations within the polycystin complex cause autosomal dominant polycystic kidney disease (ADPKD). The spatial and temporal regulation of the polycystin complex within the ciliary membrane remains poorly understood. Using both whole-cell and ciliary patch-clamp recordings, we identify a cilia-enriched oxysterol, 7β,27-dihydroxycholesterol (DHC), that serves as a necessary activator of the polycystin complex. We further identify an oxysterol-binding pocket within PC-2 and showed that mutations within this binding pocket disrupt 7β,27-DHC-dependent polycystin activation. Pharmacologic and genetic inhibition of oxysterol synthesis reduces channel activity in primary cilia. In summary, our findings reveal a regulator of the polycystin complex. This oxysterol-binding pocket in PC-2 may provide a specific target for potential ADPKD therapeutics.
多囊蛋白-1（PC-1）和 PC-2 形成异源二聚体离子通道复合物，该复合物在肾脏上皮细胞的初级纤毛中大量表达。该复合物作为一种非选择性阳离子通道发挥作用，多囊蛋白复合物内的突变导致常染色体显性多囊肾病（ADPKD）。多囊蛋白复合物在纤毛膜内的时空调节仍知之甚少。我们使用全细胞和纤毛膜片钳记录技术，鉴定出一种富含纤毛的氧化固醇，即 7β,27-二羟胆固醇（DHC），它是多囊蛋白复合物的必需激活剂。我们进一步在 PC-2 内鉴定出一个氧化固醇结合口袋，并表明该结合口袋内的突变会破坏 7β,27-DHC 依赖的多囊蛋白激活。氧化固醇合成的药理学和遗传学抑制会降低初级纤毛中的通道活性。总之，我们的研究结果揭示了多囊蛋白复合物的一种调节剂。PC-2 中的这个氧化固醇结合口袋可能为潜在的 ADPKD 治疗提供一个特定的靶点。
