Autosomal dominant polycystic kidney disease, a common cause of renal failure, arises from mutations in either the PKD1 or the PKD2 gene. The precise function of both PKD gene products polycystins (PCs) 1 and 2 remain controversial. PC2 has been localized to numerous cellular compartments, including the endoplasmic reticulum, plasma membrane, and cilia. 2؉ transients. However, overexpressing the disease-associated PC2 mutants, the point mutation D511V, and the C-terminally truncated mutation R742X did not alter the t1 ⁄ 2 . In addition, we found that D511V overexpression significantly reduced the amplitude of IP 3 -induced Ca 2؉ transients. Interestingly, overexpression of the C terminus of PC2 not only significantly reduced the amplitude but also prolonged the t1 ⁄ 2 . Coimmunoprecipitation assays indicated that PC2 physically interacts with IP 3 R through its C terminus. Taken together, our data suggest that PC2 and IP 3 R functionally interact and modulate intracellular Ca 2؉ signaling. Therefore, mutations in either PC1 or PC2 could result in the misregulation of intracellular Ca 2؉ signaling, which in turn could contribute to the pathology of autosomal dominant polycystic kidney disease.
Autosomal dominant polycystic kidney disease (ADPKD)2 is one of the most common causes of renal failure (1). It arises from mutations in either the PKD1 or the PKD2 genes (1-5). The primary phenotype of ADPKD is the presence of numerous fluid-filled cysts in the kidney, liver, pancreas, and intestine (4). Mutations in PKD1 account for the majority (ϳ85%) of ADPKD cases and are associated with more severe clinical presentations and an earlier onset of renal failure (1, 2, 4, 5). Although both PKD genes have been identified, the molecular mechanisms leading to these clinical symptoms are still not fully clear. Hence, it is important to understand the biological roles of the PKD gene products polycystins (PCs) 1 and 2.PC1 is a 4,302-amino-acid integral membrane protein that has 11 putative transmembrane domains, a long extracellular N terminus, and a short intracellular C terminus (6). The large extracellular portion contains a novel combination of motifs originally found in other proteins that are predicted to be involved in cell-cell and cell-matrix interactions (1-3, 6, 7). Its C terminus contains a coiled-coil domain responsible for interacting with PC2 (8, 9). PC2 is a 968-amino-acid protein containing six transmembrane domains (10). Transmembrane domains 5 and 6 share a significant similarity with TRPC1, a member of the transient receptor potential cation channel family (10 -12). Both the N and the C termini are cytosolic. The C terminus of PC2 contains an ER retention signal, an EF-hand motif, and a coiled-coil domain (10, 11, 13). Electrophysiological studies indicate that PC2 is a Ca 2ϩ -activated, non-selective cation channel with multiple subconductance states and a high permeability to Ca 2ϩ (14 -17). Although it is well accepted that PC1 is expressed in the plasma membrane, the subcellular localization of PC2 has ...
