Autosomal dominant polycystic kidney disease (ADPKD) develops due to loss of function mutations in the PKD1 and PKD2 genes, which encode PC1 and PC2, respectively. PC1 is a 460kD multi‐spanning membrane protein that undergoes multiple proteolytic cleavages, at least two of which release C‐terminal fragments. Polycystin 1 and Polycystin 2 both prominently localize to the primary cilium where they contribute to cellular mechano‐sensation and also form a cation‐permeable heterotetrameric channel that may contribute to Ca2+ flux into the cilia. Recent studies demonstrate that PC1 can function as an atypical adhesion GPCR that is activated by Wnt ligands. Wnt ligand binding leads to dissociation of the PC1 extracellular N terminal fragment and allows the PC1 receptor function to be activated by a tethered agonist peptide that resides at the N terminus of the PC1 transmembrane domains.Here we report that Polycystin 1 cilia and cell surface localization is regulated by its activity status. We demonstrate that a constitutively active form of the Polycystin 1 protein is absent from the primary cilia whereas a constitutively inactive version of the PC1 protein that lacks its tethered agonist peptide resides in the primary cilia. Moreover, we show that interruption of the cellular receptor desensitization process by β‐arrestin inhibition permits the constitutively active PC1 construct to accumulate in the cilium. We also studied the surface localization of the full length PC1 and found that extended Wnt9b ligand treatment or mechanical stimulation both lead to reduced quantity of the full length PC1 at the cell surface and in the primary cilium, a process that can be disrupted by inhibition of β‐arrestin. In vivo, we find that reduction of the luminal flow in renal tubules by ureter obstruction leads to accumulation of the PC1 in the primary cilia of the tubule cells.Taken together, our data suggest that PC1 surface trafficking is regulated by receptor‐activating stimuli including ligand binding and mechanical stress and, similar to the regulation of aGPCR receptors, is subject to an activity‐dependent receptor desensitization process. Our findings indicate that the aGPCR receptor‐like properties of Polycystin 1 offer new insights into this protein’s physiological function and the regulation of its trafficking. Understanding these processes may suggest targets for the development of new therapeutic interventions for ADPKD.
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