Recent data indicate that polycystin-2 (TRPP2, an ion channel of the TRP-superfamily) can interact with the inositol 1,4,5-trisphosphate receptor (IP₃R). In this study we aimed to specify the exact interaction sites for polycystin-2 as well as for the IP₃R and to investigate the functional relevance of their interaction.

Via immunoprecipitation of polycystin-2 from extracts of the LLC-PK1 renal cell line stably expressing full-length polycystin-2, we could detect interaction with full-length IP₃R3, which is the main IP₃R isoform present in these cells. Further analysis by GST-pull-down assays revealed that the C-terminal cytoplasmic tail of polycystin-2 (aa 679-966) strongly interacted with the N-terminal ligand-binding domain (LBD) of the IP₃R1 (aa 1-581). Moreover, the C-terminal tail of polycystin-2 inhibited the binding of IP₃ to this LBD with an IC₅₀ ~350 nM. We demonstrated that the suppressor region of IP₃R1 (aa 1-225) was necessary for this inhibitory effect of polycystin-2 on IP₃ binding.

We therefore conclude that direct interaction between polycystin-2 and the IP₃R can be important for modulating intracellular Ca²⁺ signalling. Disturbance of the intracellular Ca²⁺ signalling could be one mechanism for the development of autosomal dominant polycystic kidney disease caused by loss-of-function mutations in polycystin-2.