Journal article
Cleavage of N-terminus of polycystin-1 increases calcium permeability of polycystin-1/2 receptor channel complexes
JCI insight, Vol.10(19), e185186
10/08/2025
DOI: 10.1172/jci.insight.185186
PMCID: PMC12513491
PMID: 40892463
Abstract
Mutations on genes encoding polycystin-1 (PC1) and -2 (PC2) cause autosomal-dominant polycystic kidney disease. How these two proteins work together to exert anti-cystogenesis remains elusive. PC1 resembles adhesion G-protein coupled receptors and undergoes autocleavage in the extracellular N-terminus to expose a hidden "stalk" region, which is hypothesized to act as a "tethered agonist". Here, we showed that wildtype PC1 and PC2 formed functional heteromeric channel complexes in Xenopus 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 impacting ion selectivity of the complexes. .
Details
- Title: Subtitle
- Cleavage of N-terminus of polycystin-1 increases calcium permeability of polycystin-1/2 receptor channel complexes
- Creators
- Runping Wang - University of IowaDanish Idrees - University of IowaMohammad Amir - University of IowaBiswajit Padhy - University of IowaJian Xie - University of IowaChou-Long Huang - University of Iowa
- Resource Type
- Journal article
- Publication Details
- JCI insight, Vol.10(19), e185186
- DOI
- 10.1172/jci.insight.185186
- PMID
- 40892463
- PMCID
- PMC12513491
- NLM abbreviation
- JCI Insight
- ISSN
- 2379-3708
- eISSN
- 2379-3708
- Publisher
- AMER SOC CLINICAL INVESTIGATION INC
- Grant note
- Jared and Carol Hills
We thank Alan Yu and Julie Xia Zhou (University of Kansas Medical Center, Kansas City, Kansas, USA) for PKD plasmids, Thoms Carroll (UT Southwestern Medical Center, Dallas, Texas, USA) for Wnt9B plas-mid. This work was supported, in part, by philanthropic gifts from Jared and Carol Hills.
- Language
- English
- Electronic publication date
- 09/02/2025
- Date published
- 10/08/2025
- Academic Unit
- Nephrology; Internal Medicine
- Record Identifier
- 9984958294002771
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