The cytoplasmic C-terminal fragment of polycystin-1 regulates a Ca2+-permeable cation channel

The cytoplasmic C-terminal portion of the polycystin-1 polypeptide (PKD1(1- 226)) regulates several important cell signaling pathways, and its deletion suffices to cause autosomal dominant polycystic kidney disease, However, a functional link between PKD1 and the ion transport processes required to d rive renal cyst enlargement has remained elusive, We report here that expre ssion at the Xenopus oocyte surface of a transmembrane fusion protein encod ing the C-terminal portion of the PKD1 cytoplasmic tail, PKD1(115-226), but not the N-terminal portion, induced a large, Ca2+-permeable cation current , which shifted oocyte reversal potential (E-rev) by +33 mV, Whole cell cur rents were sensitive to inhibition by La3+, Gd3+, and Zn2+, and partially i nhibited by SKF96365 and amiloride, Currents were not activated by bath hyp ertonicity, but were inhibited by acid pH, Outside-out patches pulled from PKD1(115-226)-expressing oocytes exhibited a 5.1-fold increased NP, of endo genous 20-picosiemens cation channels of linear conductance. PKD1(115-226)- injected oocytes also exhibited elevated NPo of unitary calcium currents in outside-out and cell-attached patches, and elevated calcium permeability d ocumented by fluorescence ratio and Ca-45(2+) flux experiments. Both Ca2+ c onductance and influx were inhibited by La3+, Mutation of candidate phospho rylation sites within PKD1(115-226) abolished the cation current. We conclu de that the C-terminal cytoplasmic tail of PKD1 up-regulates inward current that includes a major contribution from Ca2+-permeable nonspecific cation channels. Dysregulation of these or similar channels in autosomal dominant polycystic kidney disease may contribute to cyst formation or expansion.