Polycystin-1 and -2 Dosage Regulates Pressure Sensing

• Published in: Cell Vol. 139; no. 3; pp. 587 - 596
• Main Authors: Sharif-Naeini, Reza, Folgering, Joost H.A., Bichet, Delphine, Duprat, Fabrice, Lauritzen, Inger, Arhatte, Malika, Jodar, Martine, Dedman, Alexandra, Chatelain, Franck C., Schulte, Uwe, Retailleau, Kevin, Loufrani, Laurent, Patel, Amanda, Sachs, Frederick, Delmas, Patrick, Peters, Dorien J.M., Honoré, Eric
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 30.10.2009; Elsevier
• Subjects: Actins - metabolism; Animals; Biochemistry, Molecular Biology; Biophysics; Cell Behavior; CELLBIO; Cellular Biology; Contractile Proteins - metabolism; Filamins; Genomics; Immunology; Life Sciences; Mechanotransduction, Cellular; Medication; Mice; Microfilament Proteins - metabolism; Molecular biology; Muscle, Smooth, Vascular - metabolism; Myocytes, Smooth Muscle - metabolism; Neurobiology; Neurons and Cognition; Pharmaceutical sciences; Pharmacology; Pressoreceptors - metabolism; Pressure; SIGNALING; Subcellular Processes; TRPP Cation Channels - metabolism; CELLBIO; SIGNALING
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2009.08.045

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.