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Articles in PresS, published online ahead of print December 18, 2001
Physiol Genomics, 10.1152/physiolgenomics.00092.2001
Submitted on October 2, 2001
Accepted on December 6, 2001
1 Molecular Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA; Medicine, Harvard Medical School, Boston, MA, USA
2 Molecular Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA
3 Genzyme Corporation, Framingham, MA, USA
4 Molecular Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA; Renal Units, Beth Israel Deaconess Medical Center, Boston, MA, USA; Cell Biology, Harvard Medical School, Boston, MA, USA
* To whom correspondence should be addressed. E-mail: salper{at}caregroup.harvard.edu.
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 C-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, co-expression of a fusion protein expressing the interacting C-terminal cytoplasmic tail of PKD2 did suppress cation current. Liganding of the ecto-domain 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.
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