Abstract
The human genome contains approximately 800 G protein-coupled receptors (GPCRs), all characterized by a common 7-transmembrane domain architecture. Here, we show that PKD1, an 11-transmembrane protein with a noncanonical transient receptor potential (TRP) channel architecture, functions as a GPCR with unique biochemical properties. PKD1 acts as a WNT-activated receptor, directly coupling to heterotrimeric Gαi1-3 subunits to inhibit cellular cAMP accumulation. While PKD1 contains both ligand-binding and G protein recruitment sites, PKD2, an associating TRP channel subunit, chaperones PKD1 to the plasma membrane to operate as a GPCR. This represents a striking departure from classical GPCR architecture and expands the functional repertoire of the TRP channel family. Given that mutations in either PKD1 or PKD2 are linked to autosomal dominant polycystic kidney disease, a multisystemic disorder marked by elevated cAMP levels, our results provide molecular insights into disease pathogenesis and highlight potential new therapeutic avenues for this debilitating and costly condition.
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Acknowledgements
We would like to thank Drs. P. DeAngelis and X. Zhang for comments on the manuscript; Dr. Feng Qian for human HA-tagged PKD1 and PKD1-T3049V, Dr. Chris Ward for PKD1-eGFP, and Dr. Wenhan Chang for CaSR. This work was supported by grant number R01DK59599 (LT) and the John S. Gammill Endowed Chair in Polycystic Kidney Disease (LT); F31DK30605 (EPH); R35GM142786 (WLB), R01MH125998 (MA), U54DK126126 (SCP), and R01GM104251 (AAP).
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E.P.H.: performed BRET experiments, analyzed data, and wrote the paper with L.T. A.N.H.: performed imaging experiments. M.M.P.: constructed and characterized the PKD2-CRISPR-KO construct. V.N.: performed immunoblotting experiments on wild-type and PKD1 variants. S.E.G.: prepared PyMOL structures. WLB: assisted with molecular cloning. A.A.P., M.A., H.T.M.H., and S.C.P.: provided reagents. L.T.: supervised the project and wrote the paper with E.P.H.
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Hardy, E.P., Haider, A.N., Patel, M.M. et al. A heteromeric TRP channel that functions as a WNT-activated G protein-coupled receptor. Nat Commun (2026). https://doi.org/10.1038/s41467-026-69932-w
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DOI: https://doi.org/10.1038/s41467-026-69932-w
