Identification of a PY motif in the epithelial Na channel subunits as a target sequence for mutations causing channel activation found in Liddle syndrome.

Schild, Laurent; Lu, Yin; Gautschi, Ivan; Schneeberger, Estelle; Lifton, Richard P.; Rossier, Bernard C.

doi:10.1002/j.1460-2075.1996.tb00594.x

Cited by 377 publications

(310 citation statements)

References 18 publications

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“…Results of alanine scanning mutagenesis within this region in the presence of an intact ␤ subunit PY motif suggested that this region did not participate in the control of amiloride-sensitive currents in channels with otherwise intact C termini (35). However, it is possible that this region is involved in channel regulation under specific conditions, such as in the presence of arachidonic acid.…”

Section: Discussionmentioning

confidence: 99%

Arachidonic Acid Regulates Surface Expression of Epithelial Sodium Channels

Carattino¹,

Hill²,

Kleyman

2003

Journal of Biological Chemistry

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Epithelial Na ؉ channels (ENaCs) are regulated by the phospholipase A 2 (PLA 2 ) product arachidonic acid. Pharmacological inhibition of PLA 2 with aristolochic acid induced a significant increase in amiloride-sensitive currents in Xenopus oocytes expressing ENaC. Arachidonic acid or 5,8,11,14-eicosatetraynoic acid (ETYA), a non-metabolized analog of arachidonic acid, induced a time-dependent inhibition of Na ؉ transport. These effects were also observed by co-expression of a calcium-independent or a calcium-dependent PLA 2 . Channels with a truncated ␣, ␤, or ␥ C terminus were not inhibited by arachidonic acid or ETYA.

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Section: Discussionmentioning

confidence: 99%

Arachidonic Acid Regulates Surface Expression of Epithelial Sodium Channels

Carattino¹,

Hill²,

Kleyman

2003

Journal of Biological Chemistry

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“…Because the Nedd4-2-mediated inhibition of ENaC requires the presence of PY motifs in the C termini of ENaC, we tested the effect of SGK1 on mutated ENaC channels with C-terminal deletions in all three subunits. The sites of the C-terminal truncations were analogous to the original Liddle's syndrome mutation of the ␤-subunit and resulted in the loss of all PY motifs (36). As shown in Fig.…”

Section: Deletion Of the C Termini Of All Three Enac Subunits Abolishmentioning

confidence: 93%

“…Those encoding the truncated rENaC subunits ␣ P646stop , ␤ R564stop , and ␥ F606stop (36) and the mutant subunit ␤ S518C (37) were in pSD5 and were a gift of Drs. Bernard C. Rossier and Laurent Schild (Lausanne, Switzerland).…”

Section: Methodsmentioning

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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“…Liddle's syndrome mutations affect the cytoplasmic tail of ENaC subunits, altering or deleting a crucial PPPXY motif essential for interaction with WW domains of Nedd4-2 (and a homologue Nedd4-1) and degradation as well as for internalization via clathrin-coated pits (Schild et al 1995). The mutated ENaC channel subunits in Liddle's syndrome are no longer recycled, and the fraction at the luminal cell surface increases (Fig.…”

Section: Liddle's Syndromementioning

confidence: 99%

Genetics of arterial hypertension and hypotension

Rosskopf

Schürks

Rimmbach

et al. 2007

Naunyn-Schmied Arch Pharmacol

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Human hypertension affects affects more than 20% of the adult population in industrialized countries, and it is implicated in millions of deaths worldwide each year from stroke, heart failure and ischemic heart disease. Available evidence suggests a major genetic impact on blood pressure regulation. Studies in monogenic hypertension revealed that renal salt and volume regulation systems are predominantly involved in the genesis of these disorders. Mutations here affect the synthesis of mineralocorticoids, the function of the mineralocorticoid receptor, epithelial sodium channels and their regulation by a new class of kinases, termed WNK kinases. It has been learned from monogenic hypotension that almost all ion transporters involved in the renal uptake of Na + have a major impact on blood pressure regulation. For essential hypertension as a complex disease, many candidate genes have been analysed. These include components of the reninangiotensin-aldosterone system, adducin, β-adrenoceptors, G protein subunits, regulators of G protein signalling (RGS) proteins, Rho kinases and G protein receptor kinases. At present, the individual impact of common polymorphisms in these genes on the observed blood pressure variation, on risk for stroke and as predictors of antihypertensive responses remains small and clinically irrelevant. Nevertheless, these studies have greatly augmented our knowledge on the regulation of renal functions, cellular signal transduction and the integration of both. Together, this provides the basis for the identification of novel drug targets and, hopefully, innovative antihypertensive drugs.

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Identification of a PY motif in the epithelial Na channel subunits as a target sequence for mutations causing channel activation found in Liddle syndrome.

Cited by 377 publications

References 18 publications

Arachidonic Acid Regulates Surface Expression of Epithelial Sodium Channels

Arachidonic Acid Regulates Surface Expression of Epithelial Sodium Channels

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

Genetics of arterial hypertension and hypotension

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