Role of SGK in hormonal regulation of  epithelial sodium channel in A6 cells

Rosa, Diego Álvarez de la; Canessa, Cecilia M.

doi:10.1152/ajpcell.00398.2002

Cited by 82 publications

(89 citation statements)

References 33 publications

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“…Some studies suggest that aldosterone does not regulate the sodium channel pool in the early stages (26). Others conclude that the effect is due exclusively to an increase in channel density (27), and that aldosterone, vasopressin, and insulin act on sodium transport by promoting the incorporation of channels in the apical membrane (28). Conversely, several groups have suggested that aldosterone increases the ENaC open probability (15), possibly by posttranslational modification (26,29).…”

Section: Resultsmentioning

confidence: 99%

Aldosterone acts via an ATP autocrine/paracrine system: The Edelman ATP hypothesis revisited

Gorelik

Zhang

Sánchez

et al. 2005

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

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Aldosterone, the most important sodium-retaining hormone, was first characterized >50 years ago. However, despite numerous studies including the classical work of Isidore S. ''Izzy'' Edelman showing that aldosterone action depended on ATP production, the mechanism by which it activates sodium reabsorption via the epithelial sodium channel remains unclear. Here, we report experiments that suggest that one of the key steps in aldosterone action is via an autocrine͞paracrine system. The hormone stimulates ATP release from the basolateral side of the target kidney cell. Prevention of ATP accumulation or its removal blocks aldosterone action. ATP then acts via a purinergic mechanism to produce contraction of small groups of adjacent epithelial cells. Patch clamping demonstrates that it is these contracted cells that have channel activity. With progressive recruitment of contracting cells, there is then a parallel increase in transepithelial electrical conductance. In common with other stimuli of sodium transport, this pathway involves phosphatidylinositol 3-kinase. Inhibition of phosphatidylinositol 3-kinase blocks both cell contraction and conductance. We put forward the hypothesis that redistribution of the cell volume caused by the lateral contraction results in apical swelling and that this change, in turn, disrupts the epithelial sodium channel interaction with the F-actin cytoskeleton, opening the channel and hence increasing sodium transport.scanning ion conductance microscopy ͉ scanning probe microscopy ͉ epithelial sodium channel ͉ renal epithelium T he sodium homeostasis regulatory hormone aldosterone was first identified in 1953 (1). Early studies on the biochemical mechanism of its action were reviewed by Edelman and Fimognari (2). This work was greatly helped by the introduction by Ussing and Zerahn (3) of the short-circuit current method for measuring sodium transport. Jean Crabbé (4, 5) first demonstrated the effect of aldosterone on sodium transport across toad bladder and skin and drew attention to the latent period of 60-90 min in the action of aldosterone. He postulated the synthesis or activation of an intermediate by aldosterone. Work by Edelman et al. (6) showed that inhibition of DNA-dependent RNA synthesis and of protein synthesis blocked the aldosterone effect. Edelman et al. (6) went on to demonstrate that aldosterone activation of sodium transport was critically dependent on ATP production. In substrate-depleted toad bladders, aldosterone had little or no effect, but the response was restored by adding glucose or pyruvate to the medium. Edelman suggested that a possible explanation of this absolute dependence on substrate was that, in the energy-depleted system, the rate of activation of sodium transport was limited by the local concentration of ATP. However, he felt that this hypothesis was questionable given that substrate-depleted toad bladders responded to vasopressin and to amphotericin B with a normal increase in sodium transport. This work became known as the ATP generation hypothe...

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Section: Resultsmentioning

confidence: 99%

Aldosterone acts via an ATP autocrine/paracrine system: The Edelman ATP hypothesis revisited

Gorelik

Zhang

Sánchez

et al. 2005

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

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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).…”

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confidence: 99%

“…This has been reported to result in an inhibition of Nedd4-2-mediated ubiquitination, endocytic retrieval, and proteasomal degradation of ENaC, thereby increasing the number of functional ENaC channels in the plasma membrane (27,28). However, there is disagreement as to whether the stimulatory effect of SGK1 on ENaC surface expression is primarily mediated by a decrease in removal from or an increase in translocation to the plasma membrane (23,29). Finally, in addition to its stimulatory effect on ENaC surface expression, SGK1 may also increase ENaC open probability (30).…”

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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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“…In the early phase of induction, aldosterone activates preexisting ENaC channels through transcriptional regulation of proteins that stimulate ENaC activity. Serum and glucocorticoid regulated kinase 1 (SGK1) is now recognized as a prototypic early-response gene and a key mediator of the stimulatory effects of aldosterone on ENaC activity in CCD cells (1,8,17,27).…”

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confidence: 99%