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Stefan Somlo - One of the best experts on this subject based on the ideXlab platform.
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disrupting Polycystin 2 ef hand ca2 affinity does not alter channel function or contribute to polycystic kidney disease
Journal of Cell Science, 2020Co-Authors: Thuy N. Vien, Stefan Somlo, Peter C Harris, Jessica M Smith, Ke Dong, Matteus Krappitz, Vladimir G Gainullin, Sorin V Fedeles, Paul G. DecaenAbstract:Approximately 15% of autosomal dominant polycystic kidney disease (ADPKD) is caused by variants in PKD2. PKD2 encodes Polycystin-2, which forms an ion channel in primary cilia and endoplasmic reticulum (ER) membranes of renal collecting duct cells. Elevated internal Ca2+ modulates Polycystin-2 voltage dependent gating and subsequent desensitization— two biophysical regulatory mechanisms that control its function at physiological membrane potentials. Here, we refute the hypothesis that Ca2+ occupancy of the polycytsin-2 intracellular EF hand is responsible for these forms of channel regulation, and if disrupted, results in ADPKD. We identify and introduce mutations that attenuate Ca2+-EF hand affinity but find channel function is unaltered in the primary cilia and ER membranes. We generated two new mouse strains that harbor distinct mutations that abolish Ca2+-EF hand association but do not result in a PKD phenotype. Our findings suggest additional Ca2+ binding sites within Polycystin-2 or Ca2+-dependent modifiers are responsible for regulating channel activity.
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Polycystin 1 a master regulator of intersecting cystic pathways
Trends in Molecular Medicine, 2014Co-Authors: Sorin V Fedeles, Annarachel Gallagher, Stefan SomloAbstract:Autosomal dominant polycystic kidney disease (ADPKD) is the most common potentially lethal monogenic disorder, with more than 12 million cases worldwide. The two causative genes for ADPKD, PKD1 and PKD2, encode protein products Polycystin-1 (PC1) and Polycystin-2 (PC2 or TRPP2), respectively. Recent data have shed light on the role of PC1 in regulating the severity of the cystic phenotypes in ADPKD, autosomal recessive polycystic kidney disease (ARPKD), and isolated autosomal dominant polycystic liver disease (ADPLD). These studies showed that the rate for cyst growth was a regulated trait, a process that can be either sped up or slowed down by alterations in functional PC1. These findings redefine the previous understanding that cyst formation occurs as an 'on-off' process. Here, we review these and other related studies with an emphasis on their translational implications for polycystic diseases.
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a genetic interaction network of five genes for human polycystic kidney and liver diseases defines Polycystin 1 as the central determinant of cyst formation
Nature Genetics, 2011Co-Authors: Sorin V Fedeles, Lin Geng, Yiqiang Cai, Xin Tian, Annarachel Gallagher, Michihiro Mitobe, Saori Nishio, Seung Hun Lee, Craig M Crews, Stefan SomloAbstract:Autosomal dominant polycystic liver disease results from mutations in PRKCSH or SEC63. The respective gene products, glucosidase IIβ and SEC63p, function in protein translocation and quality control pathways in the endoplasmic reticulum. Here we show that glucosidase IIβ and Sec63p are required in mice for adequate expression of a functional complex of the polycystic kidney disease gene products, Polycystin-1 and Polycystin-2. We find that Polycystin-1 is the rate-limiting component of this complex and that there is a dose-response relationship between cystic dilation and levels of functional Polycystin-1 following mutation of Prkcsh or Sec63. Reduced expression of Polycystin-1 also serves to sensitize the kidney to cyst formation resulting from mutations in Pkhd1, the recessive polycystic kidney disease gene. Finally, we show that proteasome inhibition increases steady-state levels of Polycystin-1 in cells lacking glucosidase IIβ and that treatment with a proteasome inhibitor reduces cystic disease in orthologous gene models of human autosomal dominant polycystic liver disease.
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mechanical stimuli induce cleavage and nuclear translocation of the Polycystin 1 c terminus
Journal of Clinical Investigation, 2004Co-Authors: Veronique Chauvet, David H. Grimm, Xin Tian, Oxana Ibraghimovbeskrovnaya, Herve Husson, Tong Wang, Thomas Hieseberger, Peter Igarashi, Anton M Bennett, Stefan SomloAbstract:Polycystin-1, which is encoded by a gene that is mutated in autosomal dominant polycystic kidney disease (ADPKD), is involved in cell-matrix interactions as well as in ciliary signaling. The precise mechanisms by which it functions, however, remain unclear. Here we find that Polycystin-1 undergoes a proteolytic cleavage that releases its C-terminal tail (CTT), which enters the nucleus and initiates signaling processes. The cleavage occurs in vivo in association with alterations in mechanical stimuli. Polycystin-2, the product of the second gene mutated in ADPKD, modulates the signaling properties of the Polycystin-1 CTT. These data reveal a novel pathway by which Polycystin-1 transmits messages directly to the nucleus.
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The N-terminal Extracellular Domain Is Required for Polycystin-1-dependent Channel Activity
The Journal of biological chemistry, 2004Co-Authors: Victor Babich, Stefan Somlo, Yiqiang Cai, Oxana Ibraghimov-beskrovnaya, Wei Zhong Zeng, Byung Il Yeh, Chou Long HuangAbstract:Abstract Autosomal dominant polycystic kidney disease (PKD) is caused by mutation of Polycystin-1 or Polycystin-2. Polycystin-2 is a Ca2+-permeable cation channel. Polycystin-1 is an integral membrane protein of less defined function. The N-terminal extracellular region of Polycystin-1 contains potential motifs for protein and carbohydrate interaction. We now report that expression of Polycystin-1 alone in Chinese hamster ovary (CHO) cells and in PKD2-null cells can confer Ca2+-permeable non-selective cation currents. Co-expression of a loss-of-function mutant of Polycystin-2 in CHO cells does not reduce Polycystin-1-dependent channel activity. A Polycystin-1 mutant lacking ∼2900 amino acids of the extracellular region is targeted to the cell surface but does not produce current. Extracellular application of antibodies against the immunoglobulin-like PKD domains reduces Polycystin-1-dependent current. These results support the hypothesis that Polycystin-1 is a surface membrane receptor that transduces the signal via changes in ionic currents.
Peter C Harris - One of the best experts on this subject based on the ideXlab platform.
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disrupting Polycystin 2 ef hand ca2 affinity does not alter channel function or contribute to polycystic kidney disease
Journal of Cell Science, 2020Co-Authors: Thuy N. Vien, Stefan Somlo, Peter C Harris, Jessica M Smith, Ke Dong, Matteus Krappitz, Vladimir G Gainullin, Sorin V Fedeles, Paul G. DecaenAbstract:Approximately 15% of autosomal dominant polycystic kidney disease (ADPKD) is caused by variants in PKD2. PKD2 encodes Polycystin-2, which forms an ion channel in primary cilia and endoplasmic reticulum (ER) membranes of renal collecting duct cells. Elevated internal Ca2+ modulates Polycystin-2 voltage dependent gating and subsequent desensitization— two biophysical regulatory mechanisms that control its function at physiological membrane potentials. Here, we refute the hypothesis that Ca2+ occupancy of the polycytsin-2 intracellular EF hand is responsible for these forms of channel regulation, and if disrupted, results in ADPKD. We identify and introduce mutations that attenuate Ca2+-EF hand affinity but find channel function is unaltered in the primary cilia and ER membranes. We generated two new mouse strains that harbor distinct mutations that abolish Ca2+-EF hand association but do not result in a PKD phenotype. Our findings suggest additional Ca2+ binding sites within Polycystin-2 or Ca2+-dependent modifiers are responsible for regulating channel activity.
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Regulation of Polycystin expression, maturation and trafficking.
Cellular signalling, 2020Co-Authors: Peter C HarrisAbstract:The major autosomal dominant polycystic kidney disease (ADPKD) genes, PKD1 and PKD2, are wildly expressed at the organ and tissue level. PKD1 encodes Polycystin 1 (PC1), a large membrane associated receptor-like protein that can complex with the PKD2 product, PC2. Various cellular locations have been described for both PC1, including the plasma membrane and extracellular vesicles, and PC2, especially the endoplasmic reticulum (ER), but compelling evidence indicates that the primary cilium, a sensory organelle, is the key site for the Polycystin complex to prevent PKD. As with other membrane proteins, the ER biogenesis pathway is key to appropriately folding, performing quality control, and exporting fully folded PC1 to the Golgi apparatus. There is a requirement for binding with PC2 and cleavage of PC1 at the GPS for this folding and export to occur. Six different monogenic defects in this pathway lead to cystic disease development, with PC1 apparently particularly sensitive to defects in this general protein processing pathway. Trafficking of membrane proteins, and the Polycystins in particular, through the Golgi to the primary cilium have been analyzed in detail, but at this time, there is no clear consensus on a ciliary targeting sequence required to export proteins to the cilium. After transitioning though the trans-Golgi network, Polycystin-bearing vesicles are likely sorted to early or recycling endosomes and then transported to the ciliary base, possibly via docking to transition fibers (TF). The membrane-bound Polycystin complex then undergoes facilitated trafficking through the transition zone, the diffusion barrier at the base of the cilium, before entering the cilium. Intraflagellar transport (IFT) may be involved in moving the Polycystins along the cilia, but data also indicates other mechanisms. The ciliary Polycystin complex can be ubiquitinated and removed from cilia by internalization at the ciliary base and may be sent back to the plasma membrane for recycling or to lysosomes for degradation. Monogenic defects in processes regulating the protein composition of cilia are associated with syndromic disorders involving many organ systems, reflecting the pleotropic role of cilia during development and for tissue maintenance. Many of these ciliopathies have renal involvement, likely because of faulty Polycystin signaling from cilia. Understanding the expression, maturation and trafficking of the Polycystins helps understand PKD pathogenesis and suggests opportunities for therapeutic intervention.
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A Polycystin-centric view of cyst formation and disease: the Polycystins revisited
Kidney international, 2015Co-Authors: Albert C.m. Ong, Peter C HarrisAbstract:It is 20 years since the identification of PKD1, the major gene mutated in autosomal dominant polycystic kidney disease (ADPKD), followed closely by the cloning of PKD2. These major breakthroughs have led in turn to a period of intense investigation into the function of the two proteins encoded, Polycystin-1 and Polycystin-2, and how defects in either protein lead to cyst formation and nonrenal phenotypes. In this review, we summarize the major findings in this area and present a current model of how the Polycystin proteins function in health and disease.
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human adpkd primary cyst epithelial cells with a novel single codon deletion in the pkd1 gene exhibit defective ciliary Polycystin localization and loss of flow induced ca2 signaling
American Journal of Physiology-renal Physiology, 2007Co-Authors: Sandro Rossetti, Peter C Harris, Lianwei Jiang, Ursa Brownglaberman, Angela Wandingerness, Robert L Bacallao, Seth L AlperAbstract:Autosomal dominant polycystic kidney disease (ADPKD) gene products Polycystin-1 (PC1) and Polycystin-2 (PC2) colocalize in the apical monocilia of renal epithelial cells. Mouse and human renal cell...
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loss of Polycystin 1 in human cyst lining epithelia leads to ciliary dysfunction
Journal of The American Society of Nephrology, 2006Co-Authors: Surya M Nauli, Peter C Harris, Sandro Rossetti, Robert J Kolb, Francis J Alenghat, Mark B Consugar, Donald E Ingber, Mahmoud Loghmanadham, Jing ZhouAbstract:A “two-hit” hypothesis predicts a second somatic hit, in addition to the germline mutation, as a prerequisite to cystogenesis and has been proposed to explain the focal nature for renal cyst formation in autosomal dominant polycystic kidney disease (ADPKD). It was reported previously that Pkd1 null/null mouse kidney epithelial cells are unresponsive to flow stimulation. This report shows that Pkd1 +/null cells are capable of responding to mechanical flow stimulation by changing their intracellular calcium concentration in a manner similar to that of wild-type cells. This paper reports that human renal epithelia require a higher level of shear stress to evoke a cytosolic calcium increase than do mouse renal epithelia. Both immortalized and primary cultured renal epithelial cells that originate from normal and nondilated ADPKD human kidney tubules display normal ciliary expression of the Polycystins and respond to fluid-flow shear stress with the typical change in cytosolic calcium. In contrast, immortalized and primary cultured cyst-lining epithelial cells from ADPKD patients with mutations in PKD1 or with abnormal ciliary expression of Polycystin-1 or -2 were not responsive to fluid shear stress. These data support a two-hit hypothesis as a mechanism of cystogenesis. This report proposes that calcium response to fluid-flow shear stress can be used as a readout of Polycystin function and that loss of mechanosensation in the renal tubular epithelia is a feature of PKD cysts.
Jing Zhou - One of the best experts on this subject based on the ideXlab platform.
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retromer associates with the cytoplasmic amino terminus of Polycystin 2
Journal of Cell Science, 2018Co-Authors: Frances C Tilley, Jing Zhou, Matthew Gallon, Chong Luo, Chris M Danson, Peter J CullenAbstract:Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic human disease, with around 12.5 million people affected worldwide. ADPKD results from mutations in either PKD1 or PKD2, which encode the atypical G-protein coupled receptor Polycystin-1 (PC1) and the transient receptor potential channel Polycystin-2 (PC2), respectively. Although altered intracellular trafficking of PC1 and PC2 is an underlying feature of ADPKD, the mechanisms which govern vesicular transport of the Polycystins through the biosynthetic and endosomal membrane networks remain to be fully elucidated. Here, we describe an interaction between PC2 and retromer, a master controller for the sorting of integral membrane proteins through the endo-lysosomal network. We show that association of PC2 with retromer occurs via a region in the PC2 cytoplasmic amino-terminal domain, independently of the retromer-binding Wiskott-Aldrich syndrome and scar homologue (WASH) complex. Based on observations that retromer preferentially interacts with a trafficking population of PC2, and that ciliary levels of PC1 are reduced upon mutation of key residues required for retromer association in PC2, our data are consistent with the identification of PC2 as a retromer cargo protein.This article has an associated First Person interview with the first author of the paper.
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Polycystins and primary cilia primers for cell cycle progression
Annual Review of Physiology, 2009Co-Authors: Jing ZhouAbstract:Polycystins are a family of eight-transmembrane proteins united by sequence homology. The name stems from the identification of mutations in genes encoding Polycystin-1 and -2 in polycystic kidney diseases. This review discusses recent topics in Polycystin research, with a focus on the role of Polycystin-1 and Polycystin-2 in primary cilia and the cell cycle. Polycystins appear to play key roles during development, but a major question is their function in mature organs. Their roles in primary cilia, shear stress sensation, alteration of intracellular calcium, and planar cell polarity are examined. The third-hit hypothesis of polycystic kidney disease is discussed.
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Nek8 Regulates the Expression and Localization of Polycystin-1 and Polycystin-2
Journal of the American Society of Nephrology : JASN, 2008Co-Authors: Eisei Sohara, Ying Luo, Jingjing Zhang, Danielle K. Manning, David R. Beier, Jing ZhouAbstract:Nek8 is a serine/threonine kinase that is mutated in the jck (juvenile cystic kidneys) mouse, a model of autosomal recessive juvenile polycystic kidney disease, but its function is poorly understood. We used the jck mouse to study the functional relationship between Nek8 and other proteins that have been implicated in polycystic kidney diseases. In the collecting tubules and collecting ducts of wild-type mice, we found that Nek8 was localized to the proximal portion of primary cilia and was weakly detected in the cytosol. In the jck mutant, however, Nek8 was found along the entire length of cilia. Coimmunoprecipitation experiments demonstrated that Nek8 interacted with Polycystin-2, but not with Polycystin-1, and that the jck mutation did not affect this interaction. Western blot analysis and real-time reverse transcriptase PCR revealed that the protein and mRNA expression of Polycystin-1 (PC1) and Polycystin-2 (PC2) were increased in jck mouse kidneys. The jck mutation also led to abnormal phosphorylatin of PC2, and this was associated with longer cilia and ciliary accumulation of PC1 and PC2. Our data suggests that Nek8 interacts with the signal transduction pathways of the Polycystins and may control the targeting of these ciliary proteins. Dysfunction Nek8 may lead to cystogenesis by altering the structure and function of cilia in the distal nephron.
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fibrocystin polyductin found in the same protein complex with Polycystin 2 regulates calcium responses in kidney epithelia
Molecular and Cellular Biology, 2007Co-Authors: Shixuan Wang, Ying Luo, Jingjing Zhang, Surya M Nauli, Patrick G Starremans, Kristina A Roberts, Jing ZhouAbstract:Recent evidence suggests that fibrocystin/polyductin (FPC), Polycystin-1 (PC1), and Polycystin-2 (PC2) are all localized at the plasma membrane and the primary cilium, where PC1 and PC2 contribute to fluid flow sensation and may function in the same mechanotransduction pathways. To further define the exact subcellular localization of FPC, the protein product encoded by the PKHD1 gene responsible for autosomal recessive polycystic kidney disease (PKD) in humans, and whether FPC has direct and/or indirect cross talk with PC2, which, in turn, is pivotal for the pathogenesis of autosomal dominant PKD, we performed double immunostaining and coimmunoprecipitation as well as a microfluorimetry study of kidney tubular epithelial cells. FPC and PC2 are found to completely or partially colocalize at the plasma membrane and the primary cilium and can be reciprocally coimmunoprecipitated. Although incomplete removal of FPC by small interfering RNA and antibody 803 to intracellular epitopes of FPC did not abolish flow-induced intracellular calcium responses, antibody 804 to extracellular epitopes of FPC blocked cellular calcium responses to flow stimulation. These findings suggest that FPC and Polycystins share, at least in part, a common mechanotransduction pathway. Inherited polycystic kidney diseases (PKD) are a large group of diseases characterized by the development of multiple fluid-filled cysts in the kidney, starting from infancy or adulthood, which gradually lead to end-stage renal disease (ESRD). About 10 percent of ESRD cases are caused by PKD. In humans, there are two major forms of PKD, i.e., autosomal dominant PKD (ADPKD)
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More than colocalizing with Polycystin-1, Polycystin-l is in the centrosome
American journal of physiology. Renal physiology, 2006Co-Authors: Eva-flore Bui-xuan, Xingzhen Chen, Jing Zhou, Catherine A. Boucher, Richard Sandford, Nuria BasoraAbstract:Polycystin-1 and Polycystin-2 are involved in autosomal dominant polycystic kidney disease by unknown mechanisms. These two proteins are located in primary cilia where they mediate mechanosensation...
Peter Koulen - One of the best experts on this subject based on the ideXlab platform.
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Polycystin 2 is an intracellular calcium release channel
Nature Cell Biology, 2002Co-Authors: Sayoko Nishimura, Ralph Witzgall, Peter Koulen, Barbara E. Ehrlich, Yoshiko Maeda, Lin Geng, Stefan SomloAbstract:Polycystin-2, the product of the gene mutated in type 2 autosomal dominant polycystic kidney disease (ADPKD), is the prototypical member of a subfamily of the transient receptor potential (TRP) channel superfamily, which is expressed abundantly in the endoplasmic reticulum (ER) membrane. Here, we show by single channel studies that Polycystin-2 behaves as a calcium-activated, high conductance ER channel that is permeable to divalent cations. Epithelial cells overexpressing Polycystin-2 show markedly augmented intracellular calcium release signals that are lost after carboxy-terminal truncation or by the introduction of a disease-causing missense mutation. These data suggest that Polycystin-2 functions as a calcium-activated intracellular calcium release channel in vivo and that polycystic kidney disease results from the loss of a regulated intracellular calcium release signalling mechanism.
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Polycystin 2 is an intracellular calcium release channel
Nature Cell Biology, 2002Co-Authors: Sayoko Nishimura, Ralph Witzgall, Peter Koulen, Barbara E. Ehrlich, Yoshiko Maeda, Lin Geng, Stefan SomloAbstract:Polycystin-2, the product of the gene mutated in type 2 autosomal dominant polycystic kidney disease (ADPKD), is the prototypical member of a subfamily of the transient receptor potential (TRP) channel superfamily, which is expressed abundantly in the endoplasmic reticulum (ER) membrane. Here, we show by single channel studies that Polycystin-2 behaves as a calcium-activated, high conductance ER channel that is permeable to divalent cations. Epithelial cells overexpressing Polycystin-2 show markedly augmented intracellular calcium release signals that are lost after carboxy-terminal truncation or by the introduction of a disease-causing missense mutation. These data suggest that Polycystin-2 functions as a calcium-activated intracellular calcium release channel in vivo and that polycystic kidney disease results from the loss of a regulated intracellular calcium release signalling mechanism.
Alessandra Boletta - One of the best experts on this subject based on the ideXlab platform.
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Polycystin 1 binds par3 apkc and controls convergent extension during renal tubular morphogenesis
Nature Communications, 2013Co-Authors: Maddalena Castelli, Manila Boca, Marco Chiaravalli, Harini Ramalingam, Isaline Rowe, Gianfranco Distefano, Thomas J Carroll, Alessandra BolettaAbstract:Loss-of-function mutations in PKD1, the gene encoding the plasma membrane receptor Polycystin-1, lead to renal cyst formation in polycystic kidney disease. Here, Castelli et al. show that Polycystin-1 interacts with the Par3 polarity complex and has a role in the morphogenesis of kidney tubules during mouse development.
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Polycystin 1 binds par3 apkc and controls convergent extension during renal tubular morphogenesis
Nature Communications, 2013Co-Authors: Maddalena Castelli, Manila Boca, Marco Chiaravalli, Harini Ramalingam, Isaline Rowe, Gianfranco Distefano, Thomas J Carroll, Alessandra BolettaAbstract:Several organs, including the lungs and kidneys, are formed by epithelial tubes whose proper morphogenesis ensures correct function. This is best exemplified by the kidney, where defective establishment or maintenance of tubular diameter results in polycystic kidney disease, a common genetic disorder. Most polycystic kidney disease cases result from loss-of-function mutations in the PKD1 gene, encoding Polycystin-1, a large receptor of unknown function. Here we demonstrate that PC-1 has an essential role in the establishment of correct tubular diameter during nephron development. Polycystin-1 associates with Par3 favouring the assembly of a pro-polarizing Par3/aPKC complex and it regulates a programme of cell polarity important for oriented cell migration and for a convergent extension-like process during tubular morphogenesis. Par3 inactivation in the developing kidney results in defective convergent extension and tubular morphogenesis, and in renal cyst formation. Our data define Polycystin-1 as central to cell polarization and to epithelial tube morphogenesis and homeostasis.
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cleavage of Polycystin 1 requires the receptor for egg jelly domain and is disrupted by human autosomal dominant polycystic kidney disease 1 associated mutations
Proceedings of the National Academy of Sciences of the United States of America, 2002Co-Authors: Feng Qian, Alessandra Boletta, Terry Watnick, Anil K Bhunia, Lijuan Liu, Ali K Ahrabi, Fang Zhou, Gregory G. GerminoAbstract:Polycystin-1 plays an essential role in renal tubular morphogenesis, and disruption of its function causes cystogenesis in human autosomal-dominant polycystic kidney disease (ADPKD). We demonstrated that Polycystin-1 undergoes cleavage at G protein coupled receptor proteolytic site in a process that requires the receptor for egg jelly domain. Most of the N-terminal fragment remains tethered at the cell surface, although a small amount is secreted. PKD1-associated mutations in the receptor for egg jelly domain disrupt cleavage, abolish the ability of Polycystin-1 to activate signal transducer and activator of transcription-1, and induce tubulogenesis in vitro. We conclude that the cleavage of Polycystin-1 is likely essential for its biologic activity.
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co assembly of Polycystin 1 and 2 produces unique cation permeable currents
Nature, 2000Co-Authors: Kazushige Hanaoka, Feng Qian, William B. Guggino, Leonidas Tsiokas, Alessandra Boletta, Anil K Bhunia, Klaus Piontek, Vikas P Sukhatme, Gregory G. GerminoAbstract:The human kidney is composed of roughly 1.2-million renal tubules that must maintain their tubular structure to function properly. In autosomal dominant polycystic kidney disease (ADPKD) cysts develop from renal tubules and enlarge independently, in a process that ultimately causes renal failure in 50% of affected individuals. Mutations in either PKD1 or PKD2 are associated with ADPKD but the function of these genes is unknown. PKD1 is thought to encode a membrane protein, Polycystin-1, involved in cell-cell or cell-matrix interactions, whereas the PKD2 gene product, Polycystin-2, is thought to be a channel protein. Here we show that Polycystin-1 and -2 interact to produce new calcium-permeable non-selective cation currents. Neither Polycystin-1 nor -2 alone is capable of producing currents. Moreover, disease-associated mutant forms of either Polycystin protein that are incapable of heterodimerization do not result in new channel activity. We also show that Polycystin-2 is localized in the cell in the absence of Polycystin-1, but is translocated to the plasma membrane in its presence. Thus, Polycystin-1 and -2 co-assemble at the plasma membrane to produce a new channel and to regulate renal tubular morphology and function.