Article

Submembraneous microtubule cytoskeleton: Interaction of TRPP2 with the cell cytoskeleton

Department of Physiology, University of Alberta, Edmonton, Canada.
FEBS Journal (Impact Factor: 3.99). 09/2008; 275(19):4675-83. DOI: 10.1111/j.1742-4658.2008.06616.x
Source: PubMed

ABSTRACT 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 · 2.08 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 · 33.12 Impact Factor
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    • "Indeed, elevating intracellular Ca2+ blocks the hair cell MET channel [47] and causes adaptation [63]. Ca2+-induced activation in TRPP2 may underlie its intracellular role as a Ca2+ release channel in endoplasmic reticulum [50], though its function is often dependent on interaction with adaptor proteins [8]. One significant difference is in the permeability to organic cations, choline and TEA being significantly permeable for the native channel [59] but not for the TRPP3 [7, 16]. "
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    ABSTRACT: This review summarizes current knowledge of the hair cell mechanotransducer channel, the ion channel responsible for detecting mechanical stimuli in the inner ear and one of the few channels whose molecular structure is still unknown. Several candidate proteins have been proposed, especially members of the transient receptor potential (TRP) channel family, but all have so far failed in one test or another. Furthermore, none has biophysical properties exactly matching the native channel. The defining features of the native mechanotransducer channel are documented, including ionic permeability, channel structure inferred from blocking agents, diversity in channel conductance, and regulation by Ca(2+), which are compared with a potential candidate, TRP channels of the polycystin family. The strengths and weaknesses of a TRP channel contender are discussed.
    Pflügers Archiv - European Journal of Physiology 06/2009; 458(6):1115-23. DOI:10.1007/s00424-009-0683-x · 3.07 Impact Factor
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