Polycystin-2 (TRPP2) functions as a nonselective cation channel. Mutations in this protein cause autosomal dominant polycystic kidney disease. Bending of the primary cilium, an organelle implicated in this disease, triggers an increase in cytosolic Ca²⁺ in renal epithelia. The Ca²⁺ permeability and cilial localization of TRPP2 make it an attractive candidate for a cilial Ca²⁺ entry pathway. However, the channel has not been shown to be mechanosensitive. We hypothesized that TRPP2 may form heteromultimeric complexes with other TRP channels to become mechanosensitive. Recent in vivo studies suggest a role for TRPV4 as an osmo- and mechanosensor. To test whether TRPV4 and TRPP2 may form a functional complex we used Xenopus oocytes. Expression of TRPV4 gave rise to steady state currents that were increased by hypotonic cell swelling. Interestingly, coexpression of TRPV4 and TRPP2 significantly increased the swelling-activated currents. We demonstrated a physical interaction between the two channels using co-immunoprecipitation and FRET. Like TRPP2, GFP-tagged TRPV4 was found at the base of cilia in polarized MDCK cells. We found that the Ca²⁺ increase upon cilial bending in MDCK cells was strongly decreased by ruthenium red, an inhibitor of TRPV4. To test for the relevance of these findings in vivo we are currently looking for genetic evidence in mice and zebrafish.