Polycystin-2, the Protein Mutated in Autosomal Dominant Polycystic Kidney Disease (ADPKD), is a Ca2+-Permeable Nonselective Cation Channel

• Published in: Proceedings of the National Academy of Sciences - PNAS 2001-01, Vol.98 (3), p.1182-1187
• Main Authors: González-Perrett, Silvia, Kim, Keetae, Ibarra, Cristina, Damiano, Alicia E., Zotta, Elsa, Batelli, Marisa, Harris, Peter C., Reisin, Ignacio L., Arnaout, M. Amin, Cantiello, Horacio F.
• Format: Article
• Language: English
• Subjects: Animals; Antibodies; Antibodies - pharmacology; Autosomal dominant polycystic kidney; Biological Sciences; Calcium; Calcium - pharmacology; Calcium Channels - drug effects; Calcium Channels - genetics; Calcium Channels - physiology; Cell Line; Cell Membrane - physiology; Complementary DNA; Cysts; Disease; Female; Gadolinium - pharmacology; Humans; Insect viruses; Ion channels; Kidneys; Lanthanum - pharmacology; Membrane Potentials - drug effects; Membrane Potentials - physiology; Membrane Proteins - drug effects; Membrane Proteins - genetics; Membrane Proteins - physiology; Mutation; Placenta; Placenta - physiology; Polycystic kidney diseases; Polycystic Kidney, Autosomal Dominant - genetics; Pregnancy; Protein Biosynthesis; Proteins; Recombinant Proteins - drug effects; Recombinant Proteins - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Spodoptera; Transfection; Trophoblasts - physiology; TRPP Cation Channels
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.021456598

Defects in polycystin-2, a ubiquitous transmembrane glycoprotein of unknown function, is a major cause of autosomal dominant polycystic kidney disease (ADPKD), whose manifestation entails the development of fluid-filled cysts in target organs. Here, we demonstrate that polycystin-2 is present in term human syncytiotrophoblast, where it behaves as a nonselective cation channel. Lipid bilayer reconstitution of polycystin-2-positive human syncytiotrophoblast apical membranes displayed a nonselective cation channel with multiple subconductance states, and a high permselectivity to Ca2+. This channel was inhibited by anti-polycystin-2 antibody, Ca2+, La3+, Gd3+, and the diuretic amiloride. Channel function by polycystin-2 was confirmed by patch-clamping experiments of polycystin-2 heterologously infected Sf9 insect cells. Further, purified insect cell-derived recombinant polycystin-2 and in vitro translated human polycystin-2 had similar ion channel activity. The polycystin-2 channel may be associated with fluid accumulation and/or ion transport regulation in target epithelia, including placenta. Dysregulation of this channel provides a mechanism for the onset and progression of ADPKD.