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WNK3 positively regulates epithelial calcium channels TRPV5 and TRPV6 via a kinase-dependent pathway

Nephrology Research and Training Center, Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama

Submitted 1 April 2008 ; accepted in final form 28 August 2008

WNK3, a member of the With No Lysine (K) family of protein serine/threonine kinases, was shown to regulate members of the SLC12A family of cation-chloride cotransporters and the renal outer medullary K⁺ channel ROMK and Cl^– channel SLC26A9. To evaluate the effect of WNK3 on TRPV5, a renal epithelial Ca²⁺ channel that serves as a gatekeeper for active Ca²⁺ reabsorption, WNK3 and TRPV5 were coexpressed in Xenopus laevis oocytes and the function and expression of TRPV5 were subsequently examined. An 82.7 ± 7.1% increase in TRPV5-mediated Ca²⁺ uptake was observed when WNK3 was coexpressed. A similar increase in TRPV5-mediated Na⁺ current was observed with the voltage-clamp technique. WNK3 also enhanced Ca²⁺ influx and Na⁺ current mediated by TRPV6, which is the closest homolog of TRPV5 that mediates active intestinal Ca²⁺ absorption. The kinase domain of WNK3 alone was sufficient to increase TRPV5-mediated Ca²⁺ transport, and the positive regulatory effect was abolished by the kinase-inactive D294A mutation in WNK3, indicating a kinase-dependent mechanism. The complexly glycosylated TRPV5 that appears at the plasma membrane was increased by WNK3. The exocytosis of TRPV5 was increased by WNK3, and the effect of WNK3 on TRPV5 was abolished by the microtubule inhibitor colchicine. The increased plasma membrane expression of TRPV5 was likely due to the enhanced delivery of mature TRPV5 to the plasma membrane from its intracellular pool via the secretory pathway. These results indicate that WNK3 is a positive regulator of the transcellular Ca²⁺ transport pathway.

calcium absorption; reabsorption; WNK4

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