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Co-assembly of polycystin-1 and -2 produces unique cation-permeable currents

Abstract

The human kidney is composed of roughly 1.2-million renal tubules that must maintain their tubular structure to function properly. In autosomal dominant polycystic kidney disease (ADPKD) cysts develop from renal tubules and enlarge independently, in a process that ultimately causes renal failure in 50% of affected individuals1,2. Mutations in either PKD1 or PKD2 are associated with ADPKD but the function of these genes is unknown. PKD1 is thought to encode a membrane protein, polycystin-1, involved in cell–cell or cell–matrix interactions3,4,5, whereas the PKD2 gene product, polycystin-2, is thought to be a channel protein6. Here we show that polycystin-1 and -2 interact to produce new calcium-permeable non-selective cation currents. Neither polycystin-1 nor -2 alone is capable of producing currents. Moreover, disease-associated mutant forms of either polycystin protein that are incapable of heterodimerization do not result in new channel activity. We also show that polycystin-2 is localized in the cell in the absence of polycystin-1, but is translocated to the plasma membrane in its presence. Thus, polycystin-1 and -2 co-assemble at the plasma membrane to produce a new channel and to regulate renal tubular morphology and function.

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Figure 1: Co-precipitation of polycystin-1 and -2.
Figure 2: Co-expression of polycystin-1 and -2 results in unique ion-channel activity.
Figure 3: Polycystin-1/2 channel is non-selective for cations.
Figure 4: Subcellular localization of CD4, polycystin-1, polycystin-2 and mutant polycystin-2 (R742X) in CHO cells by confocal imaging.
Figure 5: Disease-causing mutations disrupt complex assembly and channel activity.

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Acknowledgements

This work was supported by NIH grants (to W.G. and G.G.G.), the American Heart Association, the Polycystic Kidney Disease Research Foundation, the National Kidney Foundation and the Arrison Foundation. The authors are members of the Johns Hopkins University PKD Center of Excellence (NIH). G.G.G. is the Blum Scholar of the Johns Hopkins University School of Medicine. We thank J. Neely for immunofluorescence; M. Delannoy for confocal microscopy; A. Hazama for discussion; and S. Agarwal for technical assistance.

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Correspondence to William B. Guggino or Gregory G. Germino.

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Hanaoka, K., Qian, F., Boletta, A. et al. Co-assembly of polycystin-1 and -2 produces unique cation-permeable currents . Nature 408, 990–994 (2000). https://doi.org/10.1038/35050128

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