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Rapid actions of steroids. Focus on "Nongenomic regulation of ENaC by aldosterone"

Dan R. Halm

Department of Physiology and Biophysics, Wright State University, Dayton, Ohio 45435


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STEROID HORMONES act throughout the body altering many cellular functions. The most well-known responses involve a genomic signaling pathway that results in production of new proteins. A mounting number of examples have been elucidated showing that steroid hormones also can produce responses by nongenomic means (2). Unlike the more extensively studied cytoplasmic steroid receptors, membrane receptors for steroids initiate signaling cascades that alter function in as little as a few seconds. Aldosterone is a steroid hormone with dramatic influence on Na+ absorption across epithelia (1, 5), particularly in renal collecting ducts. Activation of apical membrane Na+ channels is a key event in the genomic signaling pathway for stimulating Na+ absorption. In the current article in focus, Zhou and Bubien (Ref. 6; see page C1118 in this issue) present evidence for rapid aldosterone activation of amiloride-sensitive epithelial Na+ channels (ENaC) by a nongenomic signaling pathway. Thus, the epithelial response to aldosterone not only involves the large number of newly synthesized proteins but also can include rapid activation of Na+ channels, leading to higher rates of electrogenic Na+ absorption.

A hallmark of steroid activation was held, until recently, to be a long delay in the onset of the response. This delay would be a consequence of the time necessary for transcribing new mRNA and subsequent translation of that message into more copies of a specific protein molecule. Based on speed of the response alone, a delay time of ~10 min roughly demarcates between nongenomic and genomic signaling pathways (2). Onset of electrogenic Na+ absorption after aldosterone stimulation generally occurs with delays of one to several hours, a time more than sufficient for protein synthesis. The range of time courses for aldosterone action through these various pathways can be illustrated by results from colonic epithelia, which also augment Na+ absorption by activating apical membrane Na+ channels. Intracellular free Ca2+ increases in human colonic epithelial cells with a delay of ~30 s after aldosterone addition, clearly consistent with a nongenomic pathway (4). After a delay of ~14 min, aldosterone stimulates K+ secretion across guinea pig distal colonic mucosa, followed about an hour later by the onset of Na+ absorption, both by genomic pathways (3). As these progressive times of onset illustrate, an aldosterone response, probably as with any steroid, could involve several distinct signaling pathways such that each might be dominant over specific time periods (2).

Zhou and Bubien (6) demonstrated aldosterone activation of ENaC in two dissimilar cell types, principal cells from renal collecting ducts and peripheral blood lymphocytes. Currents carried by Na+ through ENaC activated rapidly (<2 min) and were insensitive to inhibitors of the genomic signaling pathway. Although collecting duct principal cells are the archetype of aldosterone-sensitive Na+ absorbers, the functional consequences of ENaC in lymphocytes are incompletely understood. These Na+ channels activated rapidly by aldosterone had single-channel conductance similar to ENaC stimulated by other means, but the kinetics included coordinated openings and closings of several Na+ channels. This kinetic mode may be a specific state for nongenomic activation by aldosterone.

Zhou and Bubien (6) also uncovered a component of the nongenomic signaling pathway for aldosterone. Whereas vasopressin activates ENaC through protein kinase A-dependent phosphorylation, nongenomic aldosterone activation involves methyl esterification. A broader issue also was addressed in these experiments: what factors stopped previous investigations with aldosterone from observing this rapid activation pathway? Lowering intracellular ATP concentrations eliminated the aldosterone response, suggesting that metabolic status of the cells could influence ENaC activation. In addition, cells from rodents did not respond to aldosterone in the rapid nongenomic mode even with high intracellular ATP. Species differences may result from lack of expression for the presumed membrane receptor of aldosterone but also may occur due to other inhibitory pathways (1) that could preclude activation through this nongenomic aldosterone signaling pathway.

Influences of aldosterone on Na+ absorption now can be appreciated to occur through initiation of multiple signaling pathways that act rapidly on the target or more slowly through genomic production of new proteins. Also of potential interest for transepithelial transport processes would be direct interactions of steroids with membrane proteins, similar to progesterone modulation of GABA-receptor Cl- channels (2) and inhibition of Na+-K+-ATPase by endogenous ouabain-like compounds (5). The means by which these diverse signaling routes serve to orchestrate a cellular function such as Na+ absorption is only beginning to be pieced together. Part of that control scheme could be connections between genomic and nongenomic pathways (2). Perhaps the nongenomic pathway helps to impose the characteristic long delay before onset of Na+ absorption, seen with aldosterone, by slowing either transcription of mRNA or translation into a new protein. The study by Zhou and Bubien (6) shows that a rapid-acting, presumably membrane receptor-coupled, mechanism is part of the intricate aldosterone control process for transepithelial Na+ absorption.


    FOOTNOTES

Address for reprint requests and other correspondence: D. R. Halm, Dept. of Physiology and Biophysics, Wright State Univ., Dayton, Ohio 45435 (E-mail: dan.halm{at}wright.edu).


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REFERENCES

1.   Alvarez de la Rosa, D, Canessa CM, Fyfe GK, and Zhang P. Structure and regulation of amiloride-sensitive sodium channels. Annu Rev Physiol 62: 573-594, 2000[ISI][Medline].

2.   Falkenstein, E, Tillmann HC, Christ M, Feuring M, and Wehling M. Multiple actions of steroid hormones: a focus on rapid, nongenomic effects. Pharmacol Rev 52: 513-555, 2000[Abstract/Free Full Text].

3.   Halm, DR, and Halm ST. Aldosterone stimulates K secretion prior to onset of Na absorption in guinea pig distal colon. Am J Physiol Cell Physiol 266: C552-C558, 1994[Abstract/Free Full Text].

4.   Maguire, D, MacNamara B, Cuffe JE, Winter D, Doolan CM, Urbach V, O'Sullivan GC, and Harvey BJ. Rapid responses to aldosterone in human distal colon. Steroids 64: 51-63, 1999[ISI][Medline].

5.   Therien, AG, and Blostein R. Mechanisms of sodium pump regulation. Am J Physiol Cell Physiol 279: C541-C566, 2000[Abstract/Free Full Text].

6.   Zhou, ZH, and Bubien JK. Nongenomic regulation of ENaC by aldosterone. Am J Physiol Cell Physiol 281: C1118-C1130, 2001[Abstract/Free Full Text].


Am J Physiol Cell Physiol 281(4):C1094-C1095
0363-6143/01 $5.00 Copyright © 2001 the American Physiological Society




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