Polycystin 1 ciliary localization is controlled by mechanosensitive signaling that involves secretion of ATP

Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in the genes, that encode Polycystin1(PC1) and Polycystin 2 (PC2), respectively. PC1 is a 460kD multi-spanning membrane protein that undergoes multiple proteolytic cleavages. At least two of those cleavages release fragments of the PC1 C-terminus. A population of the PC1 protein localizes to the primary cilium where, together with PC2, it is thought to participate in cellular mechano-sensation. PC1 and PC2 can form a cation-permeable heterotetrameric channel that may regulate Ca+2 influx into the cilia. Recent studies demonstrate that PC1 can function as an atypical GPCR and that it can interact with Wnt ligands.We report that activation of the PC1 receptor function regulates its ciliary localization in cultured LLC-PK1 cells and show that this effect can be modified by ligand binding or by mechanical stimuli. The ciliary quantity of the full length PC1 is dramatically reduced by exposure to the PC1-stimulatory ligand Wnt9b. Furthermore, we show that a protein construct that corresponds to a constitutively active form of the PC1 receptor is absent from the primary cilia whereas a protein construct that corresponds to a constitutively inactive form of PC1 is prominently localized to the primary cilia. Inhibition of β-arrestin with barbadin alters the distribution of the constitutively active PC1 construct, resulting in its accumulation in the cilium. Taken together, these data suggest that the ciliary localization of PC1 is governed by its receptor activity through a mechanism that resembles that of GPCR receptor desensitization. We find that mechanical stimuli also lead to removal of PC1 from the cilium. This effect is due to mechanical stimulus-induced release of ATP into the medium. Enzymatic hydrolysis of extracellular ATP prevents the effects of mechanical stimuli on PC1 ciliary localization, whereas addition of exogenous ATP to the medium is sufficient to induce departure of PC1 from the cilium in the absence of mechanical stimuli. We show that both Wnt9b and mechanical stimuli exert their effects on PC1 ciliary localization through the β-arrestin dependent cascade. These findings illuminate an exciting and largely untapped aspect of PC1 biology. NIH RO1 DK072612 and DOD PR191158 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.