TRPP2 and TRPV4 form a polymodal sensory channel complex.
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.
Köttgen
Michael
M
Renal Division, University Hospital Freiburg, 79106 Freiburg, Germany.
Buchholz
Björn
B
Garcia-Gonzalez
Miguel A
MA
Kotsis
Fruzsina
F
Fu
Xiao
X
Doerken
Mara
M
Boehlke
Christopher
C
Steffl
Daniel
D
Tauber
Robert
R
Wegierski
Tomasz
T
Nitschke
Roland
R
Suzuki
Makoto
M
Kramer-Zucker
Albrecht
A
Germino
Gregory G
GG
Watnick
Terry
T
Prenen
Jean
J
Nilius
Bernd
B
Kuehn
E Wolfgang
EW
Walz
Gerd
G
D000818:Animals; D020013:Calcium Signaling; D002460:Cell Line; D002923:Cilia / Q000378:metabolism; D003560:Cysts / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism; D006801:Humans; D009865:Oocytes / Q000378:metabolism; D011485:Protein Binding; D021381:Protein Transport; D050396:TRPP Cation Channels / Q000378:metabolism*; D050916:TRPV Cation Channels / Q000378:metabolism*; D013696:Temperature
D050396:TRPP Cation Channels; D050916:TRPV Cation Channels; C486576:Trpv4 protein, mouse