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Cation channel regulation by COOH-terminal cytoplasmic tail of polycystin-1: mutational and functional analysis

¹ Molecular Medicine
² Renal Units, Beth Israel Deaconess Medical Center
³ Departments of Medicine
⁴ Cell Biology, Harvard Medical School, Boston 02215
⁵ Genzyme Corporation, Framingham, Massachusetts 01701-9322

Polycystin-1 (PKD1) mutations account for 85% of autosomal dominant polycystic kidney disease (ADPKD). We have shown previously that oocyte surface expression of a transmembrane fusion protein encoding part of the cytoplasmic COOH terminus of PKD1 increases activity of a Ca²⁺-permeable cation channel. We show here that human ADPKD mutations incorporated into this fusion protein attenuated or abolished encoded cation currents. Point mutations and truncations showed that cation current expression requires integrity of a region encompassing the putative coiled coil domain of the PKD1 cytoplasmic tail. Whereas these loss-of-function mutants did not exhibit dominant negative phenotypes, coexpression of a fusion protein expressing the interacting COOH-terminal cytoplasmic tail of PKD2 did suppress cation current. Liganding of the ectodomain of the PKD1 fusion protein moderately activated cation current. The divalent cation permeability and pharmacological profile of the current has been extended. Inducible expression of the PKD1 fusion in EcR-293 cells was also associated with activation of cation channels and increased Ca²⁺ entry.

Xenopus oocyte; EcR-293 cells; polycystin-2; 2-aminophenylborate; intracellular calcium; autosomal dominant polycystic kidney disease

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