Submembraneous microtubule cytoskeleton: Interaction of TRPP2 with the cell cytoskeleton

Department of Physiology, University of Alberta, Edmonton, Canada.
FEBS Journal (Impact Factor: 4). 09/2008; 275(19):4675-83. DOI: 10.1111/j.1742-4658.2008.06616.x
Source: PubMed


TRPP2, also called polycystin-2, the gene product of PKD2, is a membrane protein defective in 10-15% of cases of autosomal dominant polycystic kidney disease. Mutations in PKD2 are also associated with extrarenal disorders, such as hepatic cystogenesis and cardiovascular abnormalities. TRPP2 is a Ca-permeable nonselective cation channel present in the endoplasmic reticulum and plasma membrane, as well as in cilia of renal epithelial and embryonic nodal cells, in which it likely forms part of a flow sensor. Recent studies have identified a number of TRPP2-interacting proteins, of which many are cytoskeletal components. Work from our and other laboratories indicates that cytoskeletal partner proteins seem to play important, albeit highly complex, roles in the regulation of TRPP2 expression, localization and channel function. This minireview covers current knowledge about cytoskeletal interactions with TRPP2, and suggests that mutations in proteins of the TRPP2-cytoskeleton complex may be implicated in the pathogenesis of autosomal dominant polycystic kidney disease.

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    • "In this family, there are six transmembrane domains plus one N-terminal and one C-terminal intracellular domains (Mochizuki et al., 1996). It functions as a calcium-permeable cation channel that mediates calcium fluxes across plasma membrane (Chen et al., 2008), Gene 476 (2011) 38–45 Abbreviations: ADPKD, autosomal dominant polycystic kidney; ESRD, end-stage renal disease; RNAi, RNA interference; siRNA, small interfering RNA; shRNA, short hairpin RNA; ER, endoplasmic reticulum; PI3R, type I inositol 1,4,5-triphosphate receptor; EST, Expressed Sequence Tags; RACE, Rapid Amplification of cDNA Ends; PI, propidium iodide; PERK, pancreatic ER-resident eIF2 kinase; TRPP, transient receptor potential polycystic. "
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    ABSTRACT: Mutations in the PKD2 gene cause autosomal dominant polycystic kidney disease (ADPKD), a common, inherited disease that frequently leads to end-stage renal disease (ESRD). Swine show substantial similarity to humans physiologically and anatomically, and are therefore a good model system in which to decipher the structure and function of the PKD2 gene and to identify potential therapeutic targets. Here we report the cloning and characterization of the porcine PKD2 cDNA showing that the full-length gene (3370 bases) is highly expressed in kidney, with minimal expression in the liver. RNA interference (RNAi) is a promising tool to enable identification of the essential components necessary for exploitation of the pathway involved in cellular processes. We therefore designed four shRNAs and nine siRNAs targeting the region of the porcine PKD2 gene from exons 3 to 9, which is supposed to be a critical region contributing to the severity of ADPKD. The results from HeLa cells with the dual-luciferase reporter system and porcine kidney cells (LLC-PK1) showed that sh12 could efficiently knock down the PKD2 gene with an efficiency of 51% and P1 and P2 were the most effective siRNAs inhibiting 85% and 77% respectively of PKD2 expression compared with untreated controls. A subsequent functional study of the transient receptor potential polycystic (TRPP) 2 channel protein indicated that the decreased expression of TRPP2 induced by siRNA P1 and P2 could release the arrest of the cell cycle from G0/G1 promoting progression to S and G2 phases. Our data, therefore, provides evidence of potential knock-down target sites in the PKD2 gene and paves the way for the future generation of transgenic ADPKD knock-down animal models.
    Gene 05/2011; 476(1-2):38-45. DOI:10.1016/j.gene.2011.01.017 · 2.14 Impact Factor
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    • "TRPP1 interacts with TRPP2, a six transmembrane domain protein of the TRP ion channel family (for review see Giamarchi et al., 2006). Polycystins also interact with multiple partners , including the TRP channel subunits TRPC1 and TRPV4 (Kottgen et al., 2008; Tsiokas et al., 1999), as well as several elements of the cytoskeleton (for reviews see Chen et al., 2008; Delmas, 2004; Harris and Torres, 2009; Wilson, 2004). "
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    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.
    Cell 10/2009; 139(3):587-96. DOI:10.1016/j.cell.2009.08.045 · 32.24 Impact Factor
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    • "In renal epithelia, TRPP2, a causative gene product for autosomal polycystic kidney disease, is thought to act as a MSCC that can sense the displacement of the primary cilia caused by fluid flow (Nauli et al., 2003; Witzgall, 2007). The physical interaction of TRPP2 protein with TRPP1 and cytoskeletal components such as Hax-1, CD2AP, troponin I, tropomyosin-1, KIF3, mDia1, and α-actinin may be important for this mechanotransduction (Witzgall, 2007; Chen et al., 2008; Fig. 1Bd). A more recent study has revealed that TRPP2 may also form a functional heterooligomer via assembling with TRPV4 which is expressed in renal primary cilia and exhibits both mechano-and thermosensitivity (Kottgen et al., 2008). "
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    ABSTRACT: Transient receptor potential (TRP) proteins constitute a large non-voltage-gated cation channel superfamily, activated polymodally by various physicochemical stimuli, and are implicated in a variety of cellular functions. Known activators for TRP include not only chemical stimuli such as receptor stimulation, increased acidity and pungent/cooling agents, but temperature change and various forms of mechanical stimuli such as osmotic stress, membrane stretch, and shear force. Recent investigations have revealed that at least ten mammalian TRPs exhibit mechanosensitivity (TRPC1, 5, 6; TRPV1, 2, 4; TRPM3, 7; TRPA1; TRPP2), but the mechanisms underlying it appear considerably divergent and complex. The proposed mechanisms are associated with lipid bilayer mechanics, specialized force-transducing structures, biochemical reactions, membrane trafficking and transcriptional regulation. Many of mechanosensitive (MS)-TRP channel likely undergo multiple regulations via these mechanisms. In the cardiovascular system in which hemodynamic forces constantly operate, the impact of mechanical stress may be particularly significant. Extensive morphological and functional studies have indicated that several MS-TRP channels are expressed in cardiac muscle, vascular smooth muscle, endothelium and vasosensory neurons, each differentially contributing to cardiovascular (CV) functions. To further complexity, the recent evidence suggests that mechanical stress may synergize with neurohormonal mechanisms thereby amplifying otherwise marginal responses. Furthermore, the currently available data suggest that MS-TRP channels may be involved in CV pathophysiology such as cardiac arrhythmia, cardiac hypertrophy/myopathy, hypertension and aneurysms. This review will overview currently known mechanisms for mechanical activation/modulation of TRPs and possible connections of MS-TRP channels to CV disorders.
    Pharmacology [?] Therapeutics 09/2009; 123(3-123):371-385. DOI:10.1016/j.pharmthera.2009.05.009 · 9.72 Impact Factor
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