The ins and outs of polycystin-2 as a calcium release channel.

G enetic diseases of ion channels (chan-nelopathies) have been identified rapidly over the past ten years. Most are rare disorders, but others are among the most common genetic disorders known. Frances Ashcroft summarizes mutations of various ion channel genes that result in disorders of the nervous system, skeletal muscle , heart, lungs, kidney and other organs 1. Affecting 1 in 400–1000 live births, autoso-mal dominant polycystic kidney disease (ADPKD) constitutes the most common genetic cause of kidney failure in man. ADPKD results in the formation of numerous fluid-filled cysts within the kidney and liver, enlargement of these organs and renal failure in 50% of affected individuals. ADPKD is caused by mutations in either of two genes named for the disorder, PKD1 and PKD2, which encode polycystin-1 and-2, respectively. These transmembrane proteins share some sequence similarity and physically interact at their carboxy termini, suggesting that they may form a hetero-multimeric complex that functions as a receptor or an ion channel 2. Polycystin-2 has sequence similarity to TRP genes (named for the transient receptor potential gene of Drosophila), within a putative pore-forming region. A new report on page 191 of this issue of Nature Cell Biology 3 addresses how polycystin-2 functions bio-physically as a channel, where within the cell is it localized and how it functions within the context of the whole cell. Recent studies indicate that polycystin-2 can indeed form an ion channel when expressed exogenously in Xenopus oocytes or in mammalian cell lines, or when reconstituted into lipid bilayer membranes from native placental membranes or affinity-purified protein 4–6. Koulen et al. 3 show that polycystin-2 exhibits channel behaviour reminiscent of ryanodine receptors and IP 3 receptors. ER microsomes from kidney cells that were transfected to overexpress normal or truncated polycystin-2 were fused to lipid bilayers. The wild-type protein yielded a high-conductance channel that is permeable to calcium, with open probability enhanced by calcium elevation on the cytosolic side of the membrane, setting up the possibility of positive feedback between calcium flux and channel activity. An unusual twist to the story is that the channel is also voltage-dependent, being closed whenever the cytosolic side of the membrane is made positive, relative to the opposite side. The pathogenic C-terminal truncation mutant found in some affected families exhibited altered voltage dependence and its open probability was unaffected by calcium. These functional differences tended to close the mutant channel and further suggest that polycystin-2 …