TRPP2 and TRPV4 form a polymodal sensory channel complex

Abstract

Abbreviations used in this paper: FRET, fl uorescence resonance energy transfer; hpf, hours postfertilization; MO, morpholino oligonucleotide; RR, ruthenium red; TRP, transient receptor potential.The online version of this paper contains supplemental material.

Ciliar functions in the nephron

“…Indeed, a COOH-terminal truncated TRPP2 (L703X) mutant, lacking the PKD1 putative binding region, shows normal expression in cilia [19]. Recently, we [3] and others [38] have shown that TRPP2 can form heteromeric channels with TRPC1 and TRPV4. TRPP2 and TRPC1 assemble to form a channel activated in response to G protein-coupled receptor stimulation.…”

“…Substantial evidence links transient receptor potential (TRP) channels to mechanosensation in various organisms [49]. Three TRP channels are expressed in primary cilia of cultured renal epithelial cells: TRPP2 (polycystin-2), TRPC1 (canonical-1), and TRPV4 (vanilloid-4) [3,38,56,85]. TRPP2 has been suggested to be part of the mechanosensitive apparatus of the primary cilium because mechanotransduction is abolished in the presence of specific TRPP2 antibodies or in epithelial cells isolated from TRPP2-deficient mice [48].…”

“…Altogether, these data indicate that TRPP2/TRPV4 and TRPP2/TRPC1 heteromers may be essential components of ciliary mechanotransduction, although the distinction between physical and chemical mechanisms of mechanotransduction is yet to be made. In addition, their roles remain uncertain because TRPV4 −/− [38] and TRPC1 −/− [89] do not show kidney phenotypes. Two recent studies on kidney cilium also suggest that kidney injury molecule-1 (KIM-1) [37] and the complex fibrocystin/polyductin (FPC) [77] may interact with TRPP2 and thus regulate calcium flux mediated through TRPP2 channel.…”

Transient receptor potential channelopathies

“…Although ADPKD is characterized by kidney cysts and renal failure, it leads to formation of cysts in pancreas, brain, and liver and a range of cardiovascular abnormalities [67]. ADPKD patients with TRPP1 and/or TRPP2 mutations also suffer from aneurysms, vessel rupture, and internal bleeding, suggesting that PKD1 and TRPP2 are important for the integrity of the vessel wall [29].…”

Doxycycline accelerates renal cyst growth and fibrosis in the pcy/pcy mouse model of type 3 nephronophthisis, a form of recessive polycystic kidney disease

“…Another obvious diVerence between the in vitro and the in vivo situation is the absence of Xuid Xow in the collagen gels. Arguments have been presented that primary cilia serve as mechanosensors on renal tubular epithelial cells (Nauli et al 2003;Praetorius and Spring 2001) but both for theoretical reasons (Witzgall 2005) and from experimental evidence (Davenport et al 2007;Köttgen et al 2008;Piontek et al 2007) doubts have been presented against such a model. What we did observe was that the urine of placebo-treated CD1 pcy/pcy mice contains a heat-labile, probably non-proteinaceous substance that induces a rise in the intracellular calcium concentration of LLC-PK 1 cells.…”