Polycystin-2, the protein mutated in autosomal dominant polycystic kidney disease (ADPKD), is a Ca2+-permeable nonselective cation channel.
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 perm-selectivity 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.
Laboratorio de Conales Ionicos, Departamento de Fisicoquimica y Quimica Analitica, Facultad de Farmacia y Bioquimica, Buenos Aires, Argentina.
S
S
González-Perrett
K
K
Kim
C
C
Ibarra
A E
AE
Damiano
E
E
Zotta
M
M
Batelli
P C
PC
Harris
I L
IL
Reisin
M A
MA
Arnaout
H F
HF
Cantiello
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D002118:Calcium / Q000494:pharmacology; D015220:Calcium Channels / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D002460:Cell Line; D002462:Cell Membrane / Q000502:physiology; D005260:Female; D005682:Gadolinium / Q000494:pharmacology; D006801:Humans; D007811:Lanthanum / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008565:Membrane Proteins / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D009154:Mutation; D010920:Placenta / Q000502:physiology; D016891:Polycystic Kidney, Autosomal Dominant / Q000235:genetics*; D011247:Pregnancy; D014176:Protein Biosynthesis; D011994:Recombinant Proteins / Q000187:drug effects / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018411:Spodoptera; D050396:TRPP Cation Channels; D014162:Transfection; D014327:Trophoblasts / Q000502:physiology
D000906:Antibodies; D002118:Calcium; D015220:Calcium Channels; D005682:Gadolinium; D007811:Lanthanum; D008565:Membrane Proteins; D011994:Recombinant Proteins; D050396:TRPP Cation Channels