2. Academic Validation
  3. A heteromeric TRP channel that functions as a WNT-activated G protein-coupled receptor

A heteromeric TRP channel that functions as a WNT-activated G protein-coupled receptor

  • Nat Commun. 2026 Feb 26;17(1):3233. doi: 10.1038/s41467-026-69932-w.
Emily P Hardy 1,  A Nasim Haider 1,  Maulin M Patel 1,  Vasyl Nesin 1,  Hanh T M Hoang 1,  Sandra E Gostynska 2,  William L Berry 3,  Augen A Pioszak 2,  Mohiuddin Ahmad 1,  Stephen C Parnell 4,  Leonidas Tsiokas 5
Affiliations

Affiliations

  • 1 Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
  • 2 Department of Biochemistry and Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
  • 3 Department of Surgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
  • 4 Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, KS, USA.
  • 5 Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA. [email protected].
PMID: 41748625 DOI: 10.1038/s41467-026-69932-w
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.

Figures
Products