title: TRPP2 and TRPV4 form a polymodal sensory channel complex.
abstract: 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.
authors.affiliation: Renal Division, University Hospital Freiburg, 79106 Freiburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Köttgen
authors.forename: Björn
authors.initials: B
authors.lastname: Buchholz
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Garcia-Gonzalez
authors.forename: Fruzsina
authors.initials: F
authors.lastname: Kotsis
authors.forename: Xiao
authors.initials: X
authors.lastname: Fu
authors.forename: Mara
authors.initials: M
authors.lastname: Doerken
authors.forename: Christopher
authors.initials: C
authors.lastname: Boehlke
authors.forename: Daniel
authors.initials: D
authors.lastname: Steffl
authors.forename: Robert
authors.initials: R
authors.lastname: Tauber
authors.forename: Tomasz
authors.initials: T
authors.lastname: Wegierski
authors.forename: Roland
authors.initials: R
authors.lastname: Nitschke
authors.forename: Makoto
authors.initials: M
authors.lastname: Suzuki
authors.forename: Albrecht
authors.initials: A
authors.lastname: Kramer-Zucker
authors.forename: Gregory G
authors.initials: GG
authors.lastname: Germino
authors.forename: Terry
authors.initials: T
authors.lastname: Watnick
authors.forename: Jean
authors.initials: J
authors.lastname: Prenen
authors.forename: Bernd
authors.initials: B
authors.lastname: Nilius
authors.forename: E Wolfgang
authors.initials: EW
authors.lastname: Kuehn
authors.forename: Gerd
authors.initials: G
authors.lastname: Walz
mesh_terms: 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
chemical_list: D050396:TRPP Cation Channels; D050916:TRPV Cation Channels; C486576:Trpv4 protein, mouse