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Polycystin-2 is an intracellular calcium release channel

Abstract

Polycystin-2, the product of the gene mutated in type 2 autosomal dominant polycystic kidney disease (ADPKD), is the prototypical member of a subfamily of the transient receptor potential (TRP) channel superfamily, which is expressed abundantly in the endoplasmic reticulum (ER) membrane. Here, we show by single channel studies that polycystin-2 behaves as a calcium-activated, high conductance ER channel that is permeable to divalent cations. Epithelial cells overexpressing polycystin-2 show markedly augmented intracellular calcium release signals that are lost after carboxy-terminal truncation or by the introduction of a disease-causing missense mutation. These data suggest that polycystin-2 functions as a calcium-activated intracellular calcium release channel in vivo and that polycystic kidney disease results from the loss of a regulated intracellular calcium release signalling mechanism.

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Figure 1: Expression of polycystin-2 in cell lines.
Figure 2: Polycystin-2 is a voltage-dependent ion channel that conducts divalent cations.
Figure 3: Dependence of polycystin-2 channel open probability on intracellular free calcium concentration and membrane holding potential.
Figure 4: Overexpression of polycystin-2 enhances amplitude and duration of vasopressin-induced calcium transients.
Figure 5: Polycystin-2 is expressed in the ER of native kidney.

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Acknowledgements

We thank M. Caplan, W. Echevarria and M. Nathanson for helpful discussions. We also thank P. Aronson and E.Thrower for critical reading of the manuscript; Z. Huang for the LtTA-2.22 clone, A. Cedzich for the stably transfected LtTA-2.22 cell lines and B. DeGray for technical assistance. This work was supported by grants from the National Institutes of Health to S.S. (DK57328) and B.E.E. (DK57328, GM51480) and from the American Heart Association to L.G. (9730148N) and Y.C. (0130207N). P.K. and Y.M. were supported by National Kidney Foundation Research Fellowship Awards. P.K. was supported by a BASF Scholarship. The authors are investigators in the Yale Center for the Study of Polycystic Kidney Disease (P50 DK57328).

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Correspondence to Stefan Somlo.

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Koulen, P., Cai, Y., Geng, L. et al. Polycystin-2 is an intracellular calcium release channel. Nat Cell Biol 4, 191–197 (2002). https://doi.org/10.1038/ncb754

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