WNT ligands induce Ca2+ signaling on target cells. PKD1 (Polycystin 1) is considered an orphan, atypical G protein coupled receptor complexed with TRPP2 (Polycystin 2 or PKD2), a Ca2+-permeable ion channel. Inactivating mutations in their genes cause autosomal dominant polycystic kidney disease (ADPKD), one of the most common genetic diseases. Here, we show that WNTs bind to the extracellular domain of PKD1 and induce whole cell currents and Ca2+ influx dependent on TRPP2. Pathogenic PKD1 or PKD2 mutations that abrogate complex formation, compromise cell surface expression of PKD1, or reduce TRPP2 channel activity suppress activation by WNTs. Pkd2−/− fibroblasts lack WNT-induced Ca2+ currents and are unable to polarize during directed cell migration. In Xenopus embryos, PKD1, Dishevelled 2 (DVL2), and WNT9A act within the same pathway to preserve normal tubulogenesis. These data define PKD1 as a WNT (co)receptor and implicate defective WNT/Ca2+ signaling as one of the causes of ADPKD.

Autosomal dominant polycystic kidney disease (ADPKD) is caused by inactivating mutations in (85%) or (15%). The ADPKD proteins encoded by these genes, polycystin-1 (PC1) and polycystin-2 (PC2), form a plasma membrane receptor-ion channel complex. However, the mechanisms controlling the subcellular localization of PC1 and PC2 are poorly understood. Here, we investigated the involvement of the retromer complex, an ancient protein module initially discovered in yeast that regulates the retrieval, sorting, and retrograde transport of membrane receptors. Using yeast two-hybrid, biochemical, and cellular assays, we determined that PC2 binds two isoforms of the retromer-associated protein sorting nexin 3 (SNX3), including a novel isoform that binds PC2 in a direct manner. Knockdown of SNX3 or the core retromer protein VPS35 increased the surface expression of endogenous PC1 and PC2 and and increased Wnt-activated PC2-dependent whole-cell currents. These findings indicate that an SNX3-retromer complex regulates the surface expression and function of PC1 and PC2. Molecular targeting of proteins involved in the endosomal sorting of PC1 and PC2 could lead to new therapeutic approaches in ADPKD.

Mesothelial cells are specialized epithelial cells, which line the pleural, pericardial, and peritoneal cavities. Accumulating evidence suggests that the monolayer of mesothelial cells is permeable to electrolyte and fluid, and thereby govern both fluid secretion and re-absorption in the serosal cavities. Disorders in these salt and fluid transport systems may be fundamental in the pathogenesis of pleural effusion, pericardial effusion, and ascites. In this review, we discuss the location, physiological function, and regulation of active transport (Na + -K + -ATPase) systems, cation and anion channels (Na + , K + , Cl − , and Ca 2+ channels), antiport (exchangers) systems, and symport (co-transporters) systems, and water channels (aquaporins). These secretive and absorptive pathways across mesothelial monolayer cells for electrolytes and fluid may provide pivotal therapeutical targets for novel clinical intervention in edematous diseases of serous cavities. Keywords mesothelioma; ion channel; permeability; effusion; filtration; ENaC Mesothelial cells are specialized epithelial cells that line the serous cavities, including the pleural, pericardial, and peritoneal cavities in addition to internal organs [1]. While the mesothelium was first described more than a century ago, one of its critical essential functions, namely, its active roles in transerosal transport, in particular, cavity fluid secretion and reabsorption, was long overlooked. Only in last two decades compelling evidence accumulated that mesothelial cells actively transport electrolytes and fluid and, in turn, regulate liquid volume within the cavities. The mesothelium, on the basis of recent increasing experimental evidence, both in vitro and in vivo, is less permeable to electrolytes than was previously assumed, with ion permeability characteristics similar to those in epithelia [2,3]. Herein this article we will review the expression and biophysical features of salt and fluid transport systems, both active and passive, that have been identified in mesothelial cells (Fig. 1, Tables 1 and 2). I. ION CHANNELS AND ATPASE I-1. Amiloride-Inhibitable Cation ChannelsThe epithelial sodium channel (ENaC), as a major pathway which participates in sodium movement across the apical membrane of polarized epithelial cells, has been cloned and characterized [4][5][6] ENaC subunits have been cloned to date, namely α-, β-, γ-, δ-, and ε-ENaC [7]. The biophysical properties of various ENaC channels depend on their subunit compositions. When expressed in oocytes one of "conductive" subunits (α, δ, and ε-ENaC) can form a channel sharing identical biophysical properties to three-subunit channels composed of both a "conductive" subunit and two "non-conductive" subunits, namely, β-and γ-ENaCs. When α-, β-, and γ-ENaC subunits are assembled together, the result is a 4-to 6-pS channel that is highly selective for Na + over K + . In contrast, two-subunit α β-and α γ-ENaC channels display diverse amiloride sensitivity, conductance, and Na + permeability [8]. ENaC is...

Ion channel expression and activity may be affected during tumor development and cancer growth. Activation of potassium (K(+)) channels in human breast cancer cells is reported to be involved in cell cycle progression. In this study, we investigated the effects of docetaxel on the delayed rectifier potassium current (I K) and the ATP-sensitive potassium current (I KATP) in two human breast cancer cell lines, MCF-7 and MDA-MB-435S, using the whole-cell patch-clamp technique. Our results show that docetaxel inhibited the I K and I KATP in both cell lines in a dose-dependent manner. Compared with the control at a potential of +60 mV, treatment with docetaxel at doses of 0.1, 1, 5, and 10 µM significantly decreased the I K in MCF-7 cells by 16.1 ± 3.5, 30.2 ± 5.2, 42.5 ± 4.3, and 46.4 ± 9% (n = 5, P < 0.05), respectively and also decreased the I KATP at +50 mV. Similar results were observed in MDA-MB-435S cells. The G-V curves showed no significant changes after treatment of either MCF-7 or MDA-MB-435S cells with 10 μM docetaxel. The datas indicate that the possible mechanisms of I K and I KATP inhibition by docetaxel may be responsible for its effect on the proliferation of human breast cancer cells.

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