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Abstract: FR-PO571

Molecular Basis of the Regulation of a Gain-of-Function Polycystin-2 Channel by Small Molecule Ligands

Session Information

Category: Genetic Diseases of the Kidneys

  • 1201 Genetic Diseases of the Kidneys: Cystic


  • Wang, Zhifei, St. John's University, Queens, New York, United States
  • Yu, Yong, St. John's University, Queens, New York, United States

Mutations in PKD2 gene lead to autorsomal dominant polycystic kidney disesae (ADPKD). PKD2 encodes polycystin-2 (PC2) protein. As a member of the transient receptor potential (TRP) channel superfamily, PC2 functions as a non-selective cation channel. The activation and regulation of PC2 channel is largely unknown and no small molecule ligand of PC2 has been reported.


We experssed human PC2 channel in Xenopus oocytes, and used two-electrode voltage clamp (TEVC) method to record the ion channel function.


In this work, we tested the effect of a group of know TRP channel small molecule agonists on PC2 channel funciton, and found that while most of them inhibit the activity of PC2_F604P, a gain-of-function PC2 mutant PC2 channel, some others have a dual regulating effect with low concentration further activates PC2_F604P, and high concentration leads to inactivation of the channel. We identified two distinct binding sites of the ligand in PC2_F604P that are responsible for activation and inactivation respectively. Our results also suggest that Ca2+ binding at the outer pore region is essential for ligand-induced inactivation.


These results provide structural and functional views of the interaction between PC2 and small molecule ligands and showcase how ligands can regulate channel function in unusual mechanisms.


  • NIDDK Support