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J. Biol. Chem., Vol. 279, Issue 53, 55455-55464, December 31, 2004

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Polycystin-1 Activates the Calcineurin/NFAT (Nuclear Factor of Activated T-cells) Signaling Pathway^*

Sanjeev Puri, Brenda S. Magenheimer, Robin L. Maser, Erin M. Ryan, Christopher A. Zien, Danielle D. Walker, Darren P. Wallace¶, Scott J. Hempson¶, and James P. Calvet||

From the Department of Biochemistry and Molecular Biology, ^¶Department of Internal Medicine, and the Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas 66160 and the Department of Biochemistry, Panjab University, Chandigarh 160014, India

Regulation of intracellular Ca²⁺ mobilization has been associated with the functions of polycystin-1 (PC1) and polycystin-2 (PC2), the protein products of the PKD1 and PKD2 genes. We have now demonstrated that PC1 can activate the calcineurin/NFAT (nuclear factor of activated T-cells) signaling pathway through G_q -mediated activation of phospholipase C (PLC). Transient transfection of HEK293T cells with an NFAT promoter-luciferase reporter demonstrated that membrane-targeted PC1 constructs containing the membrane proximal region of the C-terminal tail, which includes the heterotrimeric G protein binding and activation domain, can stimulate NFAT luciferase activity. Inhibition of glycogen synthase kinase-3 by LiCl treatment further increased PC1-mediated NFAT activity. PC1-mediated activation of NFAT was completely inhibited by the calcineurin inhibitor, cyclosporin A. Cotransfection of a construct expressing the G_q subunit augmented PC1-mediated NFAT activity, whereas the inhibitors of PLC (U73122) and the inositol trisphosphate and ryanodine receptors (xestospongin and 2-aminophenylborate) and a nonspecific Ca²⁺ channel blocker (gadolinium) diminished PC1-mediated NFAT activity. PC2 was not able to activate NFAT. An NFAT-green fluorescent protein nuclear localization assay demonstrated that PC1 constructs containing the C-tail only or the entire 11-transmembrane spanning region plus C-tail induced NFAT-green fluorescent protein nuclear translocation. NFAT expression was demonstrated in the M-1 mouse cortical collecting duct cell line and in embryonic and adult mouse kidneys by reverse transcriptase-PCR and immunolocalization. These data suggest a model in which PC1 signaling leads to a sustained elevation of intracellular Ca²⁺ mediated by PC1 activation of G_q followed by PLC activation, release of Ca²⁺ from intracellular stores, and activation of store-operated Ca²⁺ entry, thus activating calcineurin and NFAT.

Received for publication, March 16, 2004 , and in revised form, October 4, 2004.

^* This work was supported by National Institutes of Health Grants DK53763 and DK57301 (to J. P. C.) and DK57301 (to R. L. M.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biology and the Kidney Institute, University of Kansas Medical Center 3030, 3901 Rainbow Blvd., Kansas City, KS 66160. Tel.: 913-588-7424; Fax: 913-588-7440; E-mail: jcalvet{at}kumc.edu.

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