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Article

  • The EMBO Journal (2006) 25, 4707 - 4716
  • doi:10.1038/sj.emboj.7601357

Published online: 28 September 2006

Tissue kallikrein stimulates Ca2+ reabsorption via PKC-dependent plasma membrane accumulation of TRPV5

Dimitra Gkika1,a, Catalin N Topala1,a, Qing Chang1, Nicolas Picard2, Stéphanie Thébault1, Pascal Houillier2, Joost GJ Hoenderop1 and René J M Bindels1

  1. Department of Physiology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
  2. INSERM, Unité 652 Institut Fédératif de Recherche 58 and René Descartes University Paris, Paris, France

Correspondence to:

René J M Bindels, Department of Physiology, Radboud University Nijmegen Medical Centre, PO Box 9101, Nijmegen 6500 HB, The Netherlands. Tel.: +31 24 3614211; Fax: +31 24 3616413; E-mail: r.bindels@ncmls.ru.nl

aThese authors contributed equally to this work

Received 5 May 2006; Accepted 28 August 2006

The transient receptor potential vanilloid 5 (TRPV5) channel determines urinary Ca2+ excretion, and is therefore critical for Ca2+ homeostasis. Interestingly, mice lacking the serine protease tissue kallikrein (TK) exhibit robust hypercalciuria comparable to the Ca2+ leak in TRPV5 knockout mice. Here, we delineated the molecular mechanism through which TK stimulates Ca2+ reabsorption. Using TRPV5-expressing primary cultures of renal Ca2+-transporting epithelial cells, we showed that TK activates Ca2+ reabsorption. The stimulatory effect of TK was mimicked by bradykinin (BK) and could be reversed by application of JE049, a BK receptor type 2 antagonist. A cell permeable analog of DAG increased TRPV5 activity within 30 min via protein kinase C activation of the channel since mutation of TRPV5 at the putative PKC phosphorylation sites S299 and S654 prevented the stimulatory effect of TK. Cell surface labeling revealed that TK enhances the amount of wild-type TRPV5 channels, but not of the TRPV5 S299A and S654A mutants, at the plasma membrane by delaying its retrieval. In conclusion, TK stimulates Ca2+ reabsorption via the BK-activated PLC/DAG/PKC pathway and the subsequent stabilization of the TRPV5 channel at the plasma membrane.

  • Keywords:

    • Ca2+ homeostasis,
    • kidney,
    • G-coupled receptor,
    • plasma membrane stabilization,
    • partner protein