Here we provide evidence for a critical role of the transient receptor potential cation channel, subfamily V, member 4 (TRPV4) in normal bladder function. Immunofluorescence demonstrated TRPV4 expression in mouse and rat urothelium and vascular endothelium, but not in other cell types of the bladder. Intracellular Ca2+ measurements on urothelial cells isolated from mice revealed a TRPV4-dependent response to the selective TRPV4 agonist 4α-phorbol 12,13-didecanoate and to hypotonic cell swelling. Behavioral studies demonstrated that TRPV4–/– mice manifest an incontinent phenotype but show normal exploratory activity and anxiety-related behavior. Cystometric experiments revealed that TRPV4–/– mice exhibit a lower frequency of voiding contractions as well as a higher frequency of nonvoiding contractions. Additionally, the amplitude of the spontaneous contractions in explanted bladder strips from TRPV4–/– mice was significantly reduced. Finally, a decreased intravesical stretch-evoked ATP release was found in isolated whole bladders from TRPV4–/– mice. These data demonstrate a previously unrecognized role for TRPV4 in voiding behavior, raising the possibility that TRPV4 plays a critical role in urothelium-mediated transduction of intravesical mechanical pressure.
Thomas Gevaert, Joris Vriens, Andrei Segal, Wouter Everaerts, Tania Roskams, Karel Talavera, Grzegorz Owsianik, Wolfgang Liedtke, Dirk Daelemans, Ilse Dewachter, Fred Van Leuven, Thomas Voets, Dirk De Ridder, Bernd Nilius