Abstract: TH-PO0201
Exploring the Regulation of PKD1-Mediated G-Protein Signaling
Session Information
- ADPKD and Cystic Kidney Disease - 1
October 22, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1201 Genetic Diseases of the Kidneys: Cystic (Monogenic)
Author
- Hardy, Emily P., The University of Oklahoma Health Sciences, Oklahoma City, Oklahoma, United States
Group or Team Name
- Tsiokas Lab
Background
Understanding how mutations in PKD1 and PKD2 lead to Autosomal dominant polycystic kidney disease (ADPKD) remains a major obstacle in the search for effective therapies to treat this costly and devastating condition. This knowledge gap arises from an incomplete understanding of how the protein products of these genes (PKD1 and PKD2) function in an integrated and disease-relevant perspective. Our lab recently revealed that PKD1 and PKD2 function together to form a G protein-coupled receptor (GPCR) that is activated by secreted WNT ligands. We used this finding as a springboard to investigate the regulatory mechanisms that govern this function and the downstream events that follow.
Methods
Our approach to characterize the GPCR function of the PKD1/PKD2 complex relied on a combination of in vitro methods, including bioluminescence resonance energy transfer (BRET)-based assays, single-cell calcium imaging, live-cell imaging, and patch clamp.
Results
Following activation by different WNTs, PKD1 selectively couples to different G protein alpha subunits (namely Gi and Gq). Coupling to Gi leads to the inhibition of cAMP, whereas Gq-coupling promotes calcium mobilization. Our assays also uncovered regulatory roles for several known and previously unknown protein interactors of PKD1. These include roles in signal initiation and termination, as well as in trafficking to and from the cell surface.
Conclusion
Our results expand the current understanding of Polycystin function and regulation. This knowledge removes previously impossible technical roadblocks to determine how naturally occurring mutations alter the function of these complex molecules so the development of new and more effective treatments for ADPKD can be designed.
Funding
- NIDDK Support