Approximately 15% of autosomal dominant polycystic kidney disease (ADPKD) is caused by variants in PKD2. PKD2 encodes polycystin-2, which forms an ion channel in primary cilia and endoplasmic reticulum (ER) membranes of renal collecting duct cells. Elevated internal Ca²⁺ modulates polycystin-2 voltage-dependent gating and subsequent desensitization – two biophysical regulatory mechanisms that control its function at physiological membrane potentials. Here, we refute the hypothesis that Ca²⁺ occupancy of the polycystin-2 intracellular EF hand is responsible for these forms of channel regulation, and, if disrupted, results in ADPKD. We identify and introduce mutations that attenuate Ca²⁺-EF hand affinity but find channel function is unaltered in the primary cilia and ER membranes. We generated two new mouse strains that harbor distinct mutations that abolish Ca²⁺-EF hand association but do not result in a PKD phenotype. Our findings suggest that additional Ca²⁺-binding sites within polycystin-2 or Ca²⁺-dependent modifiers are responsible for regulating channel activity.

大约 15% 的常染色体显性多囊肾病 (ADPKD) 是由PKD2变异引起的。PKD2编码多囊蛋白-2，它在初级纤毛和肾集合管细胞的内质网 (ER) 膜中形成离子通道。升高的内部 Ca ²⁺调节多囊蛋白-2 电压依赖性门控和随后的脱敏–两种生物物理调节机制在生理膜电位下控制其功能。在这里，我们反驳这样的假设：多囊蛋白-2 细胞内 EF 手的 Ca ²⁺占据负责这些形式的通道调节，并且如果被破坏，会导致 ADPKD。我们鉴定并引入了减弱 Ca ²⁺ -EF 手亲和力的突变，但发现初级纤毛和 ER 膜中的通道功能未改变。我们培育了两种新的小鼠品系，它们具有不同的突变，可以消除 Ca ²⁺ -EF 手关联，但不会导致 PKD 表型。我们的研究结果表明，多囊蛋白-2 或Ca ^{2+依赖性修饰剂内的额外Ca 2+}结合位点负责调节通道活性。