{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,17]],"date-time":"2026-05-17T15:09:00Z","timestamp":1779030540047,"version":"3.51.4"},"reference-count":76,"publisher":"American Society for Clinical Investigation","issue":"19","license":[{"start":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T00:00:00Z","timestamp":1759881600000},"content-version":"vor","delay-in-days":36,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NA","award":["NA"],"award-info":[{"award-number":["NA"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,10,8]]},"abstract":"<jats:p>\n                    Mutations on genes encoding polycystin-1 (PC1) and PC2 cause autosomal-dominant polycystic kidney disease. How these 2 proteins work together to exert anticystogenesis remains elusive. PC1 resembles adhesion G-protein coupled receptors and undergoes autocleavage in the extracellular N-terminus to expose a hidden \u201cstalk\u201d region, which is hypothesized to act as a \u201ctethered agonist.\u201d Here, we show that WT PC1 and PC2 formed functional heteromeric channel complexes in\n                    <jats:italic>Xenopus<\/jats:italic>\n                    oocytes with different biophysical properties from PC2 homomeric channels. Deletion of PC1 N-terminus, which exposed the stalk, increased calcium permeability in PC1\/PC2 heteromers that required the presence of stalk. Extracellular application of synthetic stalk peptide increased calcium permeation in stalkless PC1\/PC2. Application of Wnt9B protein increased calcium permeability in PC1\/PC2 but not in heteromers containing cleavage-resistant mutant PC1. Wnt9B interacted with N-terminal leucine-rich repeat (LRR) of PC1. Pretreatment with LRR blunted the increase in calcium permeability by Wnt9B. Thus, PC1 and PC2 form receptor-channel complexes that is activated by exposure of the stalk region following ligand binding to the PC1 N-terminus. The stalk peptide acts as a tethered agonist to activate PC1\/PC2 by affecting ion selectivity of the complexes.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.185186","type":"journal-article","created":{"date-parts":[[2025,9,2]],"date-time":"2025-09-02T16:00:19Z","timestamp":1756828819000},"source":"Crossref","is-referenced-by-count":1,"title":["Cleavage of N-terminus of polycystin-1 increases calcium permeability of polycystin-1\/2 receptor channel 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