Published online August 11, 2008
doi:10.1083/jcb.200805124
The Journal of Cell Biology, Vol. 182, No. 3, 437-447
The Rockefeller University Press, 0021-9525 $30.00
© 2008 Köttgen et al.
TRPP2 and TRPV4 form a polymodal sensory channel complex
Michael Köttgen1,
Björn Buchholz1,
Miguel A. Garcia-Gonzalez3,
Fruzsina Kotsis1,
Xiao Fu1,
Mara Doerken1,
Christopher Boehlke1,
Daniel Steffl1,
Robert Tauber1,
Tomasz Wegierski1,
Roland Nitschke5,
Makoto Suzuki2,
Albrecht Kramer-Zucker1,
Gregory G. Germino3,
Terry Watnick3,
Jean Prenen4,
Bernd Nilius4,
E. Wolfgang Kuehn1, and
Gerd Walz1
1 Renal Division, University Hospital Freiburg, 79106 Freiburg, Germany
2 Department of Pharmacology, Jichi Medical School, Mimamikawachi, Tochigi 329-0498, Japan
3 Division of Nephrology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205
4 Laboratory of Physiology, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium
5 Department of Developmental Biology, University of Freiburg, 79104 Freiburg, Germany
Correspondence to Wolfgang Kuehn: wolfgang.kuehn{at}uniklinik-freiburg.de; or Gerd Walz: gerd.walz{at}uniklinik-freiburg.de
The primary cilium has evolved as a multifunctional cellular compartment that decorates most vertebrate cells. Cilia sense mechanical stimuli in various organs, but the molecular mechanisms that convert the deflection of cilia into intracellular calcium transients have remained elusive. Polycystin-2 (TRPP2), an ion channel mutated in polycystic kidney disease, is required for cilia-mediated calcium transients but lacks mechanosensitive properties. We find here that TRPP2 utilizes TRPV4 to form a mechano- and thermosensitive molecular sensor in the cilium. Depletion of TRPV4 in renal epithelial cells abolishes flow-induced calcium transients, demonstrating that TRPV4, like TRPP2, is an essential component of the ciliary mechanosensor. Because TRPV4-deficient zebrafish and mice lack renal cysts, our findings challenge the concept that defective ciliary flow sensing constitutes the fundamental mechanism of cystogenesis.
M. Köttgen and B. Buchholz contributed equally to this paper.
M. Köttgen's present address is Department of Biological Chemistry, Johns Hopkins School of Medicine, Baltimore, MD 21205.
B. Buchholz's present address is Department of Nephrology, Friedrich-Alexander University, 91054 Erlangen, Germany
Abbreviations used in this paper: FRET, fluorescence resonance energy transfer; hpf, hours postfertilization; MO, morpholino oligonucleotide; RR, ruthenium red; TRP, transient receptor potential.
© 2008 Köttgen et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jcb.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
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