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Trendsetters
Department of Physiology, Dartmouth Medical School, Lebanon, NH 03756
Although the central role of aldosterone in the control of epithelial sodium transport has been acknowledged for decades, many molecular steps involved in this regulation remain elusive. In general, the action of aldosterone can be divided into two phases: 1) a delayed (
6 h) effect that involves the synthesis of new transporter proteins, such as the epithelial sodium channel (ENaC) or Na-K-ATPase; and 2) an immediate or early action, through so-called early-response genes. This précis deals with the latter type—-specifically, with a recently cloned early-response gene that codes for a serine/threonine kinase, which was originally described as a serum- and glucocorticoid-induced kinase, or sgk.
An important criterion for any physiologically relevant aldosterone-induced gene is that it should regulate sodium current when coexpressed with ENaC. Using this criterion, two groups have recently reported the identity of such a gene. Chen and coworkers (1) reported that dexamethasone, a synthetic glucocorticoid, rapidly induces the expression of sgk mRNA in A6 epithelia and that aldosterone increases sgk mRNA levels (as determined by in situ hybridization) in rat kidneys in vivo. They also showed that sodium current is increased when sgk is coexpressed with ENaC in Xenopus oocytes.
Simultaneously, our group (2), using primary cultures of rabbit cortical collecting duct cells (i.e., native aldosterone-responsive epithelium) identified the sgk gene as a true aldosterone-induced early-response gene by showing that 1) induction of this gene occurs within 30 min after addition of aldosterone and is maintained for ~4 h, after which mRNA levels decline despite the continuous presence of aldosterone; 2) the induction does not involve de novo protein synthesis; and 3) coexpression of sgk in Xenopus oocytes with the three subunits of ENaC results in a significantly enhanced and specific sodium current. The induction is mediated through mineralocorticoid receptors, because an antagonist to the glucocorticoid receptor did not prevent the effect (2).
The obvious next question is, What is (are) the mechanism(s) by which sgk activates sodium current? One possible answer is through phosphorylation of serine and threonine residues on ENaC subunits. Such a mechanism would be consonant not only with the demonstrated regulation of sodium channel activity by protein kinases but also with the findings of Shimkets, Lifton, and Canessa (3) that aldosterone increases phosphorylation of serine/threonine residues on the ß- and 
-subunits of ENaC in a line of renal cells and that sgk is activated by insulin, which in turn increases phosphorylation of the same residues on the same subunits. But there are other possibilities: sgk might phosphorylate regulatory proteins that might then influence the postsynthetic structure or intracellular trafficking of ENaC. Moreover, these possibilities might not be mutually exclusive; rather, they might be activated synchronously through sgk.
Sgk might also play a role in the control of cell volume. For example, sgk mRNA is increased by shrinkage of human hepatoma cells and it is decreased by swelling of these cells (Waldegger, S., et al.. Proc. Natl. Acad. Sci. USA 94: 4440–4445, 1997). We have observed similar changes in cortical collecting duct cells.
On the basis of the data described here, we propose a critical role for sgk in the early action of aldosterone and the control of cell volume, as illustrated in Fig. 1
. Aldosterone, after combining with mineralocorticoid receptors, rapidly stimulates the expression of sgk, which then activates sodium channels and, through the consequent increase in intracellular sodium, increases cell volume. Cell swelling, on the other hand, decreases sgk and leads to the opposite chain of events, thereby restoring cell volume to normal. If correct, the model would provide a fairly rapid negative feedback system for the control of cell volume, a concept supported by our observation that sgk mRNA levels decline after ~4-h exposure to aldosterone despite the continuous presence of this mineralocorticoid (2). Further experiments will be needed to determine whether the model is correct.
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Footnotes
In this section we feature some of the latest and most striking new findings in physiology, interpreting the term "physiology" in its broadest sense. In each instance, an effort will be made to place the new findings in perspective.
Heinz Valtin
Editor, TRENDSETTERS
References
| Occasionally, the Editor of the Trendsetters section invites contributions from the authors of published scientific articles that have been identified as being of special interest. All précis to Trendsetters are by invitation only. |
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