Sci. STKE, 12 March 2002
Calcium Channels Is Kidney Disease Caused by Defective Calcium Signaling?
Polycystic kidney disease is a common cause of kidney failure. Mutations in two genes are known to produce essentially identical phenotypes: PKD1 and PKD2. The products of these two genes, polycystin-1 and polycystin-2, are transmembrane proteins that interact through their COOH-terminal domains. Although polycystin-1 is clearly localized to the plasma membrane, the distribution of polycystin-2 has been controversial (see Cahalan). Koulen et al. used epithelial cells overexpressing polycystin-2, which is classified as a member of the transient receptor potential (TRP) family of channels, to study both the function and distribution of this protein. Several lines of evidence suggested that the protein is localized to the endoplasmic reticulum (ER): (i) ER membranes contained the protein, as determined by immunofluorescent labeling of transfected cells or by cell fractionation analysis; (ii) the ER membranes of tranfected cells contained a TRP-like channel that could be detected by electrophysiological methods; (iii) fractionation of kidney tissue showed overlapping distribution of polycystin-2 and markers for ER; and (iv) polycystin-2 from kidney tissue was sensitive to endoglycosidase H, indicating that it had not proceeded past the cis Golgi. By fusing ER-containing microsomal preparations with lipid bilayers, they showed that polycystin-2 is a voltage-sensitive cation channel, activated by negative membrane potentials and by calcium when increased on the cytosolic side of the bilayers. Analysis of two mutant versions of the protein known to cause disease in humans demonstrated that one of these proteins lacked channel activity completely and the other showed altered voltage dependence and complete insensitivity to calcium. Overexpression of polycystin-2 in the cells also produced enhanced calcium signals when the cells were stimulated by a ligand that increased inositol 1,4,5-trisphosphate (IP3), suggesting that polycystin-2 may be involved in calcium-induced calcium release from the ER. These studies did not address how the interaction between polycystin-1 and polycystin-2 may affect the channel properties of polycystin-2.
M. D. Calahan, The ins and outs of polycystin-2 as a calcium release channel. Nature Cell Biol. 4, E56-E57 (2002). [Online Journal]
P. Koulen, Yl. Cai, L. Geng, Y. Maeda, S. Nishimura, R. Witzgall, B. E. Ehrlich, S. Somlo, Polycystin-2 is an intracellular calcium release channel. Nature Cell Biol. 4, 191-197 (2002). [Online Journal]
Citation: Is Kidney Disease Caused by Defective Calcium Signaling? Sci. STKE 2002, tw99 (2002).
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