Paracellular Cl
            <sup>-</sup>
            permeability is regulated by WNK4 kinase: Insight into normal physiology and hypertension

Kahle, Kristopher T.; MacGregor, Gordon G.; Wilson, Frederick H.; Hoek, Alfred N. Van; Brown, Dennis; Ardito, Thomas; Kashgarian, Michael; Giebisch, Gerhard; Hebert, Steven C.; Boulpaep, Emile L.; Lifton, Richard P.

doi:10.1073/pnas.0406172101

Cited by 152 publications

(136 citation statements)

References 37 publications

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“…A combination of in vitro phosphorylation experiments and coimmunoprecipitation of WNK4 and claudins, expressed in COS7 cells, led the authors to conclude that the increased phosphorylation of claudins observed with PHAII-mutated WNK4 resulted from a stronger interaction with claudins rather than enhanced intrinsic kinase activity. Another group confirmed the electrophysiological observations that heterologous expression of WNK4 in MDCKII cells increased Cl Ϫ permeability and that this effect was further enhanced by introducing a PHAII-causing mutation into WNK4 (55). In the renal epithelial cell line LLC-PK 1 , heterologously expressed WNK4 was reported to coimmunoprecipitate with endogenous claudin-7 (97).…”

Section: Phosphorylation Of Claudinssupporting

confidence: 68%

Biology of claudins

Angelow¹,

Ahlstrom²,

Yu³

2008

American Journal of Physiology-Renal Physiology

307

294

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Claudins are a family of tight junction membrane proteins that regulate paracellular permeability of epithelia, likely by forming the lining of the paracellular pore. Claudins are expressed throughout the renal tubule, and mutations in two claudin genes are now known to cause familial hypercalciuric hypomagnesemia with nephrocalcinosis. In this review, we discuss recent advances in our understanding of the physiological role of various claudins in normal kidney function, and in understanding the fundamental biology of claudins, including the molecular basis for selectivity of permeation, claudin interactions in tight junction formation, and regulation of claudins by protein kinases and other intracellular signals.

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Section: Phosphorylation Of Claudinssupporting

confidence: 68%

Biology of claudins

Angelow¹,

Ahlstrom²,

Yu³

2008

American Journal of Physiology-Renal Physiology

307

294

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“…WNK4 mutants that cause disease fail to inhibit the sodium chloride cotransporter, suggesting that an increase in sodium chloride cotransporter activity in the distal convoluted tubule is a cause of hypertension (7,8). Others have reported that WNK4 phosphorylates claudins 1-4, the tight-junction proteins involved in the regulation of paracellular ion permeability (9,10). The paracellular chloride permeability is greater in cells expressing WNK4 mutants than in cells expressing wild-type proteins.…”

mentioning

confidence: 99%

Antagonistic regulation of ROMK by long and kidney-specific WNK1 isoforms

Lazrak

Liu

Huang³

2006

Proc. Natl. Acad. Sci. U.S.A.

161

207

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WNK kinases are serine-threonine kinases with an atypical placement of the catalytic lysine. Intronic deletions with increased expression of a ubiquitous long WNK1 transcript cause pseudohypoaldosteronism type 2 (PHA II), characterized by hypertension and hyperkalemia. Here, we report that long WNK1 inhibited ROMK1 by stimulating its endocytosis. Inhibition of ROMK by long WNK1 was synergistic with, but not dependent on, WNK4. A smaller transcript of WNK1 lacking the N-terminal 1-437 amino acids is expressed highly in the kidney. Whether expression of the KS-WNK1 (kidney-specific, KS) is altered in PHA II is not known. We found that KS-WNK1 did not inhibit ROMK1 but reversed the inhibition of ROMK1 caused by long WNK1. Consistent with the lack of inhibition by KS-WNK1, we found that amino acids 1-491 of the long WNK1 were sufficient for inhibiting ROMK. Dietary K ؉ restriction decreases ROMK abundance in the renal cortical-collecting ducts by stimulating endocytosis, an adaptative response important for conservation of K ؉ during K ؉ deficiency. We found that K ؉ restriction in rats increased whole-kidney transcript of long WNK1 while decreasing that of KS-WNK1. Thus, KS-WNK1 is a physiological antagonist of long WNK1. Hyperkalemia in PHA II patients with PHA II mutations may be caused, at least partially, by increased expression of long WNK1 with or without decreased expression of KS-WNK1. There are four mammalian WNK family members (1). WNK1, the first member identified, is Ͼ2,100 amino acids long (2). It contains an Ϸ270-aa kinase domain located near the amino terminus (e.g., amino acids 218-491 of the rat WNK1). WNK2, 3, and 4 are products of different genes and Ϸ1,200 to 1,600 amino acids in length (1, 2). The kinase domain of the four WNKs that share 85-90% sequence identity are unique in having the catalytic lysine located in the subdomain I instead of the conserved subdomain II of most protein kinases (1-3). Other conserved domains of WNK kinases include an autoinhibitory domain, 1-2 coiled-coil domains, and multiple PXXP prolinerich motifs for potential protein-protein interaction (1-4). Beyond the aforementioned conserved domains͞motifs, sequence identity among the four WNKs is much lower and few homologous regions exist.Pseudohypoaldosteronism type II (PHA II) is an autosomaldominant disease characterized by hypertension and hyperkalemia (5). Recently, Wilson et al. (6) reported that mutations of WNK1 and WNK4 cause PHA II. Mutations in the WNK1 gene are large deletions of the first intron leading to increased expression. Mutations in the WNK4 gene are missense mutations in the coding sequence outside the protein kinase domain. Several recent studies have examined the mechanisms for hypertension and hyperkalemia in PHA II patients. WNK4 inhibits the activity of the sodium chloride cotransporter. WNK4 mutants that cause disease fail to inhibit the sodium chloride cotransporter, suggesting that an increase in sodium chloride cotransporter activity in the distal convoluted tubule is a cause of hypertens...

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“…An interesting paradigm is provided by WNK1 and WNK4, two kinases linked to Pseudohypoaldosteronism type II, an autosomal dominant disorder that leads to hypertension. WNK4 localises to tight junctions and expression of disease-causing alleles of the two kinases stimulates phosphorylation of multiple claudins and leads to increased chloride permeability [95][96][97][98][99] . While these studies indicate that claudin-mediated ion conductance is regulated, the structural changes that lead form phosphorylation of claudins to opening claudin-based pores remain to be determined.…”

mentioning

confidence: 99%

Tight junctions: from simple barriers to multifunctional molecular gates

Zihni

Mills

Matter

et al. 2016

Nat Rev Mol Cell Biol

1,146

925

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Main body of text: 5983 words 2Epithelia and endothelia separate different tissue compartments and protect multicellular organisms form the outside world. This requires the formation of tight junctions, selective gates that control paracellular diffusion of ions and solutes. Tight junctions also form the border between the apical and basolateral plasma membrane domains and are linked to the machinery that controls apicobasal polarization. Additionally, signalling networks that guide diverse cell behaviours and functions are connected to tight junctions, transmitting information to and from the cytoskeleton, nucleus and different cell adhesion complexes. Here, we discuss recent advances in our understanding of the molecular architecture and cellular functions of tight junctions.Microscopists in the 19 th century described the paracellular space between neighbouring cells within an epithelial sheet to be sealed by a "terminal bar", a structure later resolved by electron microscopy into a composite of distinct cell-cell junctions that is now called the epithelial junctional complex and is formed by tight junctions, adherens junctions and desmosomes 1,2 . As the former two junctions are more tightly associated and often reside at the apical end of the lateral membrane, they are often referred to as the apical junctional complex (however, in endothelia, tight junctions and adherens junctions can be intercalated) (Fig. 1). Tight junctions are essential for barrier formation, and their primary physiological role is to function as paracellular gates that restrict diffusion on the basis of size and charge. Selective paracellular diffusion is an essential process for the maintenance of homoeostasis in organs and tissues. Tight junctions have long been the most enigmatic of all adhesion complexes and eluded a detailed molecular and functional analysis due to their complex architecture. Recent years have witnessed the identification of a large array of components associated with tight junctions implicating these junctions in an unexpected range of different functions, thereby challenging the traditional model, in which tight junctions are considered a simple diffusion barrier formed by a rigid molecular complex. In line with these various functions, mutations in genes encoding tight junction proteins have been linked to a range of inherited human diseases. Additionally, tight junction components are known to be targeted by a number of pathogenic bacteria and viruses, which hijack tight junction proteins to enter and infect cells, or target junctional signalling mechanisms to cross tissue barriers. Although tight junctions are a vertebrate junction, many of their components and functions are evolutionarily conserved (Box 1).The main purpose of this review is to examine the recent advances in the unravelling of the molecular architecture of tight junctions and understanding their functions. We will discuss recent exciting insights into how tight junctions function as signalling platforms that guide cell behaviour and differen...

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Paracellular Cl ^- permeability is regulated by WNK4 kinase: Insight into normal physiology and hypertension

Cited by 152 publications

References 37 publications

Biology of claudins

Biology of claudins

Antagonistic regulation of ROMK by long and kidney-specific WNK1 isoforms

Tight junctions: from simple barriers to multifunctional molecular gates

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Paracellular Cl - permeability is regulated by WNK4 kinase: Insight into normal physiology and hypertension

Cited by 152 publications

References 37 publications

Biology of claudins

Biology of claudins

Antagonistic regulation of ROMK by long and kidney-specific WNK1 isoforms

Tight junctions: from simple barriers to multifunctional molecular gates

Contact Info

Product

Resources

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Paracellular Cl ^- permeability is regulated by WNK4 kinase: Insight into normal physiology and hypertension