Polycystin-1 and -2 dosage regulates pressure sensing.
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.
Sharif-Naeini
Reza
R
Institut de Pharmacologie Moléculaire et Cellulaire, UMR CNRS 6097, Université de Nice Sophia Antipolis, 06560 Valbonne, France.
Folgering
Joost H A
JH
Bichet
Delphine
D
Duprat
Fabrice
F
Lauritzen
Inger
I
Arhatte
Malika
M
Jodar
Martine
M
Dedman
Alexandra
A
Chatelain
Franck C
FC
Schulte
Uwe
U
Retailleau
Kevin
K
Loufrani
Laurent
L
Patel
Amanda
A
Sachs
Frederick
F
Delmas
Patrick
P
Peters
Dorien J M
DJ
Honoré
Eric
E
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*
D000199:Actins; D003285:Contractile Proteins; D064448:Filamins; D008840:Microfilament Proteins; D050396:TRPP Cation Channels