Effects of the Serine/Threonine Kinase SGK1 on the Epithelial Na&lt;sup&gt;+&lt;/sup&gt; Channel (ENaC) and CFTR: Implications for Cystic Fibrosis

Wagner, Carsten A.; Ott, Michael; Klingel, Karin; Beck, S.; Friedrich, Björn; Wild, Karen-Nicola; Bröer, Stefan; Moschen, I.; Albers, Alexandra; Waldegger, Siegfried; Tümmler, Burkhard; Egan, Marie E.; Geibel, John P.; Kandolf, Reinhard; Läng, Florian

doi:10.1159/000051935

Cited by 112 publications

(113 citation statements)

References 44 publications

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“…Namely, vasopressin stimulates FL-SPAK in the DCT to phosphorylate NCC, whereas it attenuates KS-SPAK to allow FL-SPAK and OSR1 to phosphorylate NKCC2 [104]. Although SGK1 was first recognized as an activator of ENaC [127], later reports also showed effects on NCC [115]. SGK1…”

Section: Spak Deficiency However Does Not Completely Inhibit Ncc Phmentioning

confidence: 99%

The sodium chloride cotransporter SLC12A3: new roles in sodium, potassium, and blood pressure regulation

Moes

Lubbe

Zietse

et al. 2013

Pflugers Arch - Eur J Physiol

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SLC12A3 encodes the thiazide-sensitive sodium chloride cotransporter (NCC), which is primarily expressed in the kidney, but also in intestine and bone. In the kidney, NCC is located in the apical plasma membrane of epithelial cells in the distal convoluted tubule. Although NCC reabsorbs only 5 to 10 % of filtered sodium, it is important for the fine-tuning of renal sodium excretion in response to various hormonal and non-hormonal stimuli. Several new roles for NCC in the regulation of sodium, potassium, and blood pressure have been unraveled recently. For example, the recent discoveries that NCC is activated by angiotensin II but inhibited by dietary potassium shed light on how the kidney handles sodium during hypovolemia (high angiotensin II) and hyperkalemia. The additive effect of angiotensin II and aldosterone maximizes sodium reabsorption during hypovolemia, whereas the inhibitory effect of potassium on NCC increases delivery of sodium to the potassium-secreting portion of the nephron. In addition, great steps have been made in unraveling the molecular machinery that controls NCC. This complex network consists of kinases and ubiquitinases, including WNKs, SGK1, SPAK, Nedd4-2, Cullin-3, and Kelch-like 3. The pathophysiological significance of this network is illustrated by the fact that modification of each individual protein in the network changes NCC activity and results in salt-dependent hypotension or hypertension. This review aims to summarize these new insights in an integrated manner while identifying unanswered questions.

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Section: Spak Deficiency However Does Not Completely Inhibit Ncc Phmentioning

confidence: 99%

The sodium chloride cotransporter SLC12A3: new roles in sodium, potassium, and blood pressure regulation

Moes

Lubbe

Zietse

et al. 2013

Pflugers Arch - Eur J Physiol

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“…The X. laevis oocyte is a commonly used expression system for human CFTR [24, 97,107,115]. Three days after injection of CFTR complementary ribonucleic acid, we examined the expression of CFTR with voltage clamp experiments.…”

Section: Cftr In the Membrane Of Xenopus Laevis Oocytesmentioning

confidence: 99%

Imaging CFTR in its native environment

Schillers¹

2007

Pflugers Arch - Eur J Physiol

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Application of atomic force microscopy (AFM) on isolated plasma membranes is a valuable method to study membrane proteins down to single-molecule level in their native environment. The cystic fibrosis transmembrane conductance regulator (CFTR), a protein of the adenosine triphosphate-binding cassette transporter superfamily, is known to play a crucial role in maintaining the salt and water balance on the epithelium and to influence processes such as cell volume regulation. A mutation in the gene encoding for CFTR results in cystic fibrosis (CF), a very common lethal genetic disease. Identification of CFTR within the cell membrane at the single-molecule level makes it feasible to visualize the distribution and organization of CFTR proteins within the cell membrane of healthy individuals and CF patients. We were able to show that human red blood cells have a CFTR distribution comparable to that of epithelial cells and that the number of CFTR in cells derived from CF patients is strongly reduced. Studies on CFTR-expressing oocytes disclose CFTR dynamics upon CFTR activation. We observed that cyclic adenosine monophosphate induces an insertion of CFTR in the plasma membrane and the formation of heteromeric CFTR-containing structures with yet unknown stoichiometry. The structure of CFTR was identified by highresolution scans of immunogold-labeled CFTR, revealing that CFTR forms a tail-to-tail dimer with a central pore. In conclusion, these studies show that AFM experiments on isolated plasma membranes allow not only quantification and localization of membrane proteins but also provide insight in their dynamics at a single-molecule level.

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“…This was initially demonstrated by co-expression experiments in Xenopus laevis oocyte (16,18,21,22) and more recently in cultured renal epithelial cells (23,24). SGK1 is thought to be an important molecular target that integrates multiple endocrine inputs regulating epithelial sodium transport (24, 25).…”

mentioning

confidence: 99%

A Novel Pathway of Epithelial Sodium Channel Activation Involves a Serum- and Glucocorticoid-inducible Kinase Consensus Motif in the C Terminus of the Channel's α-Subunit

Diakov

Korbmacher

2004

Journal of Biological Chemistry

156

145

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Aldosterone-induced serum-and glucocorticoid-inducible kinase isoform 1 (SGK1) contributes to the regulation of the epithelial sodium channel (ENaC), the activity of which is critical for long term blood pressure control. Aldosterone-induced SGK1 is thought to enhance ENaC surface expression by phosphorylating Nedd4-2 and thereby preventing ENaC retrieval and degradation. In outside-out membrane patches of Xenopus laevis oocytes heterologously expressing ENaC, amiloride-sensitive ENaC currents were enhanced by phosphatase inhibitors and were dependent on cytosolic Mg 2؉ . This indicates that a kinase is involved in channel regulation. Indeed, recombinant constitutively active SGK1, included in the pipette solution, caused a sustained 2-to 3-fold increase of ENaC currents. Deletion of the C terminus of ␣ENaC largely reduced the stimulatory effect of SGK1, whereas stimulation by SGK1 did not require the presence of the C termini of the ␤-or ␥-subunits. Replacing the serine residue Ser 621 of the SGK1 consensus motif in the C terminus of the ␣-subunit by an alanine specifically abolished the stimulatory effect of SGK. Our findings indicate that SGK1 can stimulate ENaC activity independently of an inhibition of Nedd4-2-mediated channel retrieval. This defines a novel regulatory pathway likely to be relevant for aldosterone-induced stimulation of ENaC in vivo.The appropriate regulation of the epithelial sodium channel (ENaC) 1 in the kidney is critically important for the maintenance of body sodium balance and hence for long term regulation of arterial blood pressure (1). Indeed, two human genetic diseases provide direct evidence that molecular dysfunction of ENaC has severe effects on arterial blood pressure. Loss-offunction mutations of ENaC cause urinary sodium loss, hyperkalemia, and low blood pressure in patients with pseudohypoaldosteronism type 1 (2). In contrast, gain-of-function mutations of ENaC are found in patients with so-called Liddle's syndrome (pseudohyperaldosteronism) and result in increased renal sodium re-absorption, hypokalemia, and severe arterial hypertension (3).ENaC is composed of three subunits called ␣, ␤, and ␥ (4). The C termini of the ENaC subunits each contain a proline-rich PPXY (PY) motif, which is believed to be important for interaction with the ubiquitin-protein ligases Nedd4 and Nedd4-2, promoting the ubiquitination, endocytosis, and proteasomal degradation of the channel (5-8). The functional importance of the PY motif was recognized in Liddle's syndrome where mutations and/or deletions of the PY motif in ␤ or ␥ ENaC reduce the endocytic retrieval of ENaC from the membrane (9, 10). This results in an increase in the number of ENaC channels in the membrane, which in turn is thought to cause hyperabsorption of Na ϩ and hypertension in patients with Liddle's syndrome (11,12).The most important hormone to regulate ENaC activity is the mineralocorticoid aldosterone. The effects of aldosterone include transcriptional, translational, and post-translational modifications of ENaC and inv...

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Effects of the Serine/Threonine Kinase SGK1 on the Epithelial Na<sup>+</sup> Channel (ENaC) and CFTR: Implications for Cystic Fibrosis

Cited by 112 publications

References 44 publications

The sodium chloride cotransporter SLC12A3: new roles in sodium, potassium, and blood pressure regulation

The sodium chloride cotransporter SLC12A3: new roles in sodium, potassium, and blood pressure regulation

Imaging CFTR in its native environment

A Novel Pathway of Epithelial Sodium Channel Activation Involves a Serum- and Glucocorticoid-inducible Kinase Consensus Motif in the C Terminus of the Channel's α-Subunit

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