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