title: Polycystin-1 and -2 dosage regulates pressure sensing.
abstract: Autosomal-dominant polycystic kidney disease, the most frequent monogenic cause of kidney failure, is induced by mutations in the PKD1 or PKD2 genes, encoding polycystins TRPP1 and TRPP2, respectively. Polycystins are proposed to form a flow-sensitive ion channel complex in the primary cilium of both epithelial and endothelial cells. However, how polycystins contribute to cellular mechanosensitivity remains obscure. Here, we show that TRPP2 inhibits stretch-activated ion channels (SACs). This specific effect is reversed by coexpression with TRPP1, indicating that the TRPP1/TRPP2 ratio regulates pressure sensing. Moreover, deletion of TRPP1 in smooth muscle cells reduces SAC activity and the arterial myogenic tone. Inversely, depletion of TRPP2 in TRPP1-deficient arteries rescues both SAC opening and the myogenic response. Finally, we show that TRPP2 interacts with filamin A and demonstrate that this actin crosslinking protein is critical for SAC regulation. This work uncovers a role for polycystins in regulating pressure sensing.
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire, UMR CNRS 6097, Université de Nice Sophia Antipolis, 06560 Valbonne, France.
authors.forename: Reza
authors.initials: R
authors.lastname: Sharif-Naeini
authors.forename: Joost H A
authors.initials: JH
authors.lastname: Folgering
authors.forename: Delphine
authors.initials: D
authors.lastname: Bichet
authors.forename: Fabrice
authors.initials: F
authors.lastname: Duprat
authors.forename: Inger
authors.initials: I
authors.lastname: Lauritzen
authors.forename: Malika
authors.initials: M
authors.lastname: Arhatte
authors.forename: Martine
authors.initials: M
authors.lastname: Jodar
authors.forename: Alexandra
authors.initials: A
authors.lastname: Dedman
authors.forename: Franck C
authors.initials: FC
authors.lastname: Chatelain
authors.forename: Uwe
authors.initials: U
authors.lastname: Schulte
authors.forename: Kevin
authors.initials: K
authors.lastname: Retailleau
authors.forename: Laurent
authors.initials: L
authors.lastname: Loufrani
authors.forename: Amanda
authors.initials: A
authors.lastname: Patel
authors.forename: Frederick
authors.initials: F
authors.lastname: Sachs
authors.forename: Patrick
authors.initials: P
authors.lastname: Delmas
authors.forename: Dorien J M
authors.initials: DJ
authors.lastname: Peters
authors.forename: Eric
authors.initials: E
authors.lastname: Honoré
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D003285:Contractile Proteins / Q000378:metabolism; D064448:Filamins; D040542:Mechanotransduction, Cellular; D051379:Mice; D008840:Microfilament Proteins / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D011311:Pressoreceptors / Q000378:metabolism; D011312:Pressure; D050396:TRPP Cation Channels / Q000378:metabolism*
chemical_list: D000199:Actins; D003285:Contractile Proteins; D064448:Filamins; D008840:Microfilament Proteins; D050396:TRPP Cation Channels