Surfing the lipid bilayer: how basolateral insulin receptors regulate Na+ channels in the apical cell membrane. Focus on "Real-time three-dimensional imaging of lipid signal transduction: apical membrane insertion of epithelial Na+ channels"

Florian Lang

Department of Physiology, University of Tübingen, D-72076 Tübingen, Germany

RENAL TUBULAR REABSORPTION of NaCl is decisive for NaCl balance and thus a crucial determinant for blood pressure control. Increased renal tubular reabsorption, e.g., in mineralocorticoid excess (10) or in genetic disorders leading to enhanced renal tubular Na+ reabsorption (22, 31, 40), are well known causes of hypertensive disease. Moreover, several diuretics are highly effective in antihypertensive treatment (33).

Fine-tuning of renal Na+ excretion is accomplished by tight regulation of the renal epithelial Na+ channel (ENaC) in the principal cells of the terminal nephron (7, 8). Expression of ENaC is stimulated by activation of the mineralocorticoid receptor with aldosterone (34). Mineralocorticoids also increase the transcription of the serum and glucocorticoid inducible kinase SGK1 (14, 27, 35, 40). SGK1 interacts physically with ENaC (39), but its best understood role is to increase ENaC activity indirectly by phosphorylation of the ubiquitin ligase Nedd4-2 (11, 30). Nedd4-2 ubiquitinates ENaC, thus preparing the channel protein for clearance from the cell membrane and subsequent degradation (30, 32). Phosphorylation of Nedd4-2 by SGK1 reduces the affinity of the enzyme for the target protein and thus disrupts the ubiquitination of ENaC, leading to enhanced ENaC channel protein abundance in the cell membrane (1, 9, 21, 24, 27, 35, 37). Moreover, recent evidence points to phosphorylation of the ENaC protein by SGK1 with a stimulatory effect on channel activity (12).

However, to become active, SGK1 itself requires phosphorylation through a signaling cascade that includes phosphatidylinositol (PI)3-kinase and the 3-phosphoinositide-dependent kinases PDK1 and PDK2 (3, 18, 27). The reported stimulators of SGK1 include insulin (18, 29) and insulin-like growth factor IGF1 (3, 16, 18). The receptors for insulin and IGF1 are localized at the basolateral cell membrane (4), whereas ENaC is located in the apical cell membrane (23). In theory, protein signaling components could be activated at the basolateral cell membrane, diffuse to the luminal cell membrane, and participate there in the regulation of Na+ channel activity.

In their elegant study, Blazer-Yost et al. (Ref. 5; see p. C1569 in this issue) reveal a different mechanism. They provide intriguing evidence that the phosphatidylinositol 3,4,5-trisphosphate (PIP3) generated through the activity of PI3-kinase travels within the inner leaflet of the plasma membrane from the basolateral to the apical pole of the cell. This was made possible by performing confocal microscopy with rapid image acquisition of the distribution of an EGFP-coupled biosensor for PIP3. Blazer-Yost et al. argue that the tight junctions do not interfere with the diffusion of lipid molecules within the inner leaflet of the cell membrane. Thus this signaling molecule overcomes the constraints of cellular polarization. Moreover, Blazer-Yost et al. argue that a similar spreading of PIP3 within the inner leaflet of the cell membrane may accelerate signaling in other systems, such as within neuronal cells with extended cell processes.

The mechanisms regulating ENaC in the terminal nephron are similarly employed in the regulation of intestinal transport. SGK1 is expressed in intestine (38) and was recently shown to increase the activity of the intestinal glucose transporter SGLT1 (13). Similar to the effect of SGK1 on ENaC, the stimulation of SGLT1 is due at least in part to phosphorylation of Nedd4-2 and subsequently impaired action of the ubiquitin ligase (13). Enhanced SGLT1 activity accelerates intestinal glucose absorption, presumably leading to excessive insulin release, fat deposition, and subsequent decrease of plasma glucose concentration. This triggers repeated glucose uptake and thus obesity (15). Conversely, inhibitors of SGLT1 counteract obesity (36).

Because stimulation of ENaC is expected to increase blood pressure and stimulation of SGLT1 to favor the development of obesity, SGK1 may participate in the generation of metabolic syndrome or syndrome X, a condition characterized by the coincidence of essential hypertension, procoagulant state, obesity, insulin resistance, and hyperinsulinemia (29). The condition is associated with increased morbidity and mortality as a result of cardiovascular disease (17, 25). Syndrome X and Cushing's syndrome have attributes in common (2), but plasma cortisol levels are not usually elevated in syndrome X (2). Instead, the disorder may be caused by inappropriate activity of a downstream signaling element. SGK1 is such a signaling molecule downstream of glucocorticoid receptors. Thus an SGK1 gene variant leading to increased SGK1 activity might trigger glucocorticoid actions without the need for stimulation by enhanced plasma glucocorticoid activity. In fact, a variant of the SGK1 gene leads to moderate increases in blood pressure (6) and body mass index (13).

Similar mechanisms may participate in the regulation of ion channels and transporters by SGK1, its isoforms SGK2 and SGK3, and the related kinase PKB (19, 20). The observations of Blazer-Yost et al. (5) provide significant novel insight into mechanisms that participate in the activation of those kinases by insulin and growth factors. This may be applicable to both epithelial and nonpolarized tissues. A planar membrane transcellular signaling mechanism based on lipids is likely to be much more rapid than a transcytoplasmic diffusion based on proteins.

FOOTNOTES


Address for reprint requests and other correspondence: F. Lang, Dept. for Physiology, Univ. of Tubingen, Gmelinstr. 5, D-72076 Tübingen, Germany (E-mail: florian.lang{at}uni-tuebingen.de)

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