specific association of the gene product of pkd2 with the trpc1 channel the functions of the genes pkd1 and pkd2 responsible for the majority of cases of autosomal dominant polycystic kidney disease is unknown while pkd1 encodes a large integral membrane protein containing several structural motifs found in known proteins involved in cellcell or cellmatrix interactions pkd2 has homology to pkd1 and the major subunit of the voltageactivated ca2 channels we now describe sequence homology between pkd2 and various members of the mammalian transient receptor potential channel trpc proteins thought to be activated by g proteincoupled receptor activation andor depletion of internal ca2 stores we show that pkd2 can directly associate with trpc1 but not trpc3 in transfected cells and in vitro this association is mediated by two distinct domains in pkd2 one domain involves a minimal region of 73 amino acids in the cterminal cytoplasmic tail of pkd2 shown previously to constitute an interacting domain with pkd1 however distinct residues within this region mediate specific interactions with trpc1 or pkd1 the cterminal domain is sufficient but not necessary for the pkd2trpc1 association a more nterminal domain located within transmembrane segments s2 and s5 including a putative pore helical region between s5 and s6 is also responsible for the association given the ability of the trpc to form functional homo and heteromultimeric complexes these data provide evidence that pkd2 may be functionally related to trpc proteins and suggest a possible role of pkd2 in modulating ca2 entry in response to g proteincoupled receptor activation andor store depletion