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1 Department of Physiology, University of Alabama at Birmingham, Birmingham, AL, USA
2 Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
3 Department of Cell Biology, University of Alabama at Birmingham, Birmingham, AL, USA
4 Department of Genetics and Translational Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
5 Department of Physiology, University of Alabama at Birmingham, Birmingham, AL, USA; Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
* To whom correspondence should be addressed. E-mail: pdbell{at}uab.edu.
Recent genetic analysis has identified a pivotal role of primary cilia in the pathogenesis of polycystic kidney disease (PKD). However, little is known regarding how cilia loss/dysfunction contributes to cyst development. In epithelial cells, changes in apical fluid flow induce cilia-mediated Ca2+ entry via polycystin-2 (PC2), a cation channel. The Oak Ridge Polycystic Kidney (orpk) mouse contains a mutated Tg737 gene which disrupts expression of polaris, a protein required for ciliogenesis. These studies examine the effect of cilia malformation on Ca2+ entry in orpk cilia(-) collecting duct principal cells, and in orpk cells in which wild-type Tg737 was re-introduced, orpk cilia(+). [Ca2+]i was monitored in confluent cell monolayers using fluorescence microscopy. Intrinsic apical Ca2+ entry was measured by Mn2+ quenching and Ca2+-depletion/re-addition under flow conditions below the threshold for stimulation. We found that un-stimulated apical Ca2+ entry was markedly increased in cilia(-) cells, and was sensitive to Gd3+, an inhibitor of PC2. Electrophysiological measurements demonstrate increased abundance of an apical channel, consistent with PC2, in cilia(-) cells. Immunofluorescence studies revealed that PC2, normally expressed on and at the base of cilia in orpk cilia(+) cells, was observed throughout the apical membrane in cilia(-) cells. Furthermore, cilia(-) cells displayed elevated sub-apical Ca2+ levels measured with the near-membrane Ca2+ indicator FFP-18. We propose that cilia exert a tonic regulatory influence on apical Ca2+ entry, and absence of cilia results in loss of spatial organization of PC2, causing unregulated Ca2+ entry and elevations in sub-apical [Ca2+], a factor which may contribute to cyst formation.
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