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Abstract: FR-PO300

Polycystin 1 Ciliary Localization Is Controlled by Chemo- and Mechanosensitive Signaling Processes That Involve the Machinery of GPCR Desensitization

Session Information

Category: Genetic Diseases of the Kidneys

  • 1101 Genetic Diseases of the Kidneys: Cystic


  • Gresko, Nikolay P., Yale University, New Haven, Connecticut, United States
  • Caplan, Michael J., Yale University, New Haven, Connecticut, United States

Most cases of autosomal dominant polycystic kidney disease (ADPKD) are caused by loss of function mutations in the PKD1 and PKD2 genes, which encode polycystin-1 (PC1) and polycystin-2 (PC2), respectively. PC1 is a 460kD multi-spanning membrane protein that undergoes several proteolytic cleavages, one of which occurs at G protein coupled receptor proteolytic site in the N terminus and at least two of which release C-terminal fragments. PC1 and PC2 proteins localize to the primary cilium and contribute to cellular mechano-sensation and, also form a cation-permeable heterotetrameric channel. Recent studies demonstrate that PC1 can function as an atypical GPCR for Wnt ligands.




Here we report that the receptor activity of PC1 controls its ciliary localization. PC1 receptor function can be induced by ligand or by mechanical stimuli. Bending of the primary cilium have been shown to induce the release of extracellular ATP. We find that extracellular ATP reduces PC1 ciliary localization and that the effects of mechanical stimuli on the ciliary localization of PC1 may be mediated at least in part by extracellular ATP. Consistent, we show that constitutively active PC1 receptor construct is absent from the primary cilia whereas a constitutively inactive PC1 construct resides stably in the primary cilia. When we block GPCRs desensitization with β-arrestin inhibitor barbadin, we observe active PC1 construct accumulation in the cilium. We also examined the surface localization of the full length PC1 protein co-expressed with PC2 and found that extended Wnt9b ligand treatment or mechanical stimuli both lead to reduced presence of the full length PC1 protein at the cell surface and in the primary cilium, a process that can be disrupted by inhibition of β-arrestin.


Taken together, our data suggest that PC1 localization is regulated by physiological stimuli, including ligand binding and mechanical stress, through a mechanism that is similar to the receptor desensitization processes that regulate GPCR localization. Furthermore, the ATP released in response to mechanical stimuli appears to contribute to these desensitization mechanisms, resulting in removal of PC1 from the primary cilium.


  • NIDDK Support