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Sex and Salt Hormones: Rapid Effects in Epithelia

Brian J. Harvey, Steven Condliffe and Christina M. Doolan

Wellcome Trust Cellular Physiology Research Unit, Department of Physiology, University College Cork, Ireland

	Abstract

 
Recent evidence points to protein kinase C isoforms as highly specific receptors for aldosterone and estradiol in epithelia. The end targets of the kinase activation are Na⁺/H⁺ exchange and K⁺ and Ca²⁺ channels. The physiological role of the nongenomic response is to increase electrolyte absorption and inhibit secretion in pluripotential epithelia.

	Introduction

Top Introduction Nongenomic targets of... Cell signaling responses to... Rapid nongenomic targets of... Cell signaling responses to... Common and divergent signaling... Conclusion References

 
Over the past decade, the number of reports dealing with the cell signaling aspects of fast actions of steroid hormones has multiplied without an accompanying validation of their physiological meaning. The reasons for this mismatch between signal transduction and a physiological role are, in the main, due to difficulties in identification of the "nongenomic" hormone receptor and the apparent lack of rapid in vivo effects. The understanding of the relationship between rapid cell signaling and nongenomic responses to steroid hormones requires an integrative approach in which both the measurement of the cytosolic transduction processes and the macroscopic effects are determined simultaneously in whole tissue under physiological conditions.

The classic pathway for steroid action involves the binding of hormone to a specific intracellular receptor [e.g., aldosterone binding to the cytosolic mineralocorticoid type I receptor]. The receptor-steroid complex interacts with hormone-responsive elements located within target genes, initiating transcription and de novo protein synthesis. The steroid-induced proteins influence various cell functions (Fig. 1). Genomic effects of steroid hormones are characterized by a latency of onset of 2–8 h and a sensitivity to inhibitors of transcription and translation, such as actinomycin D or cycloheximide. The genomic pathway can also be inhibited by specific antagonists of the various intracellular receptors.

View larger version (22K): [in this window] [in a new window]   FIGURE 1. Summary of the key differences between genomic and nongenomic mechanisms of steroid hormone action. The classic genomic pathway is characterized by an increase in protein synthesis, which mediates the in vivo response to the hormone some hours after hormone-receptor binding. In contrast, the nongenomic pathway is characterized by rapid second messenger activation, which leads to acute (within seconds) cellular responses. The precise nature of the receptor proteins that initiate the nongenomic pathway is unclear.

	Nongenomic targets of aldosterone

Top Introduction Nongenomic targets of... Cell signaling responses to... Rapid nongenomic targets of... Cell signaling responses to... Common and divergent signaling... Conclusion References

 
Mineralocorticoid hormones increase Na⁺ reabsorption and promote K⁺ and H⁺ secretion in high-resistance epithelia. Aldosterone is the most important mineralocorticoid released from the adrenal glands. It regulates solute reabsorption in epithelia such as distal colon and kidney, acting in both a rapid and a delayed manner to influence transport (16). The classic mechanism of aldosterone stimulation of Na⁺ reabsorption involves the activation of a genomic pathway. Over the past decade, studies have described rapid actions of aldosterone on ion transport that precede the genomic events by 2–4 h. These rapid effects consistently show a high selectivity for aldosterone over cortisol and other steroids. The rapid, nongenomic pathway offers an additional explanation for the differential effects of glucocorticoids and mineralocorticoids in Na⁺ homeostasis.

In extrarenal, nonepithelial cells, aldosterone has been reported to produce rapid in vitro effects (onset within 1–2 min) on intracellular electrolyte concentrations, cell volume, Na⁺/H⁺ exchange, and inositol 1,4,5-trisphosphate production in human mononuclear leukocytes (17). Rapid effects of aldosterone on free intracellular Ca²⁺ concentration ([Ca²⁺]_i), phospholipase C, diacylglycerol, and protein kinase C (PKC) have been demonstrated in endothelial and vascular smooth muscle cells (17). In vascular tissue, the rapid responses to aldosterone may be important in the acute control of blood pressure (17).

Mammalian distal colon is a major target for aldosterone action (6), and the level of mineralocorticoid receptor gene expression is higher in the distal colon than in other target tissues such as the kidney or hippocampus (7). Recent studies from our laboratory (4, 5, 11) have demonstrated rapid (<1 min) nongenomic activation of Na⁺/H⁺ exchange, K⁺ recycling, and PKC activity, specifically by mineralocorticoids (glucocorticoids were without effect) in human and rat distal colon. The primary ion transport target of the nongenomic signal transduction cascades elicited by aldosterone in epithelia is the Na⁺/H⁺ exchanger at the basolateral cell membrane. In isolated colonic crypts, aldosterone produces an intracellular alkalinization within 1 min of hormone addition (17). Inhibition of PKC activity prevents the cellular alkalinization induced by aldosterone. Because serine kinases are important regulators of the Na⁺/H⁺ exchanger, it is likely that rapid activation of PKC by aldosterone mediates the nongenomic stimulation of the exchanger. The effect of aldosterone on Na⁺/H⁺ exchange appears to be ubiquitous in mineralocorticoid-receptive epithelia such as human sweat gland, renal collecting duct, and amphibian skin (8, 9, 15).

In pluripotential epithelia (tissues capable of simultaneous secretion and absorption), the rapid activation of Na⁺/H⁺ exchange and the resulting intracellular alkalinization have important consequences for transepithelial ion transport. An increase in intracellular pH (pH_i) produces opposite effects on two classes of basolateral K⁺ channels: an ATP-sensitive K⁺ (K_ATP) channel and a Ca²⁺-sensitive K⁺ (K_Ca) channel. The K_ATP channel is stimulated by increases in pH_i, and this channel is involved in K⁺ recycling to maintain the electrical driving force for amiloride-sensitive Na⁺ absorption. In contrast, the K_Ca channels are inhibited by cellular alkalinization, and these channels generate the charge balance for Cl^– secretion (11). At physiological concentrations (0.1–1 nM), aldosterone activates the K_ATP conductance and inhibits the K_Ca conductance within 5 min in human distal colon (11). Stimulation of PKC and Na⁺/H⁺ exchanger activity are required for these rapid effects. Thus it would appear that the nongenomic response to aldosterone in pluripotential epithelia is to enhance the capacity for absorption while downregulating the potential for secretion (Fig. 2).

View larger version (23K): [in this window] [in a new window]   FIGURE 2. The role of salt-retaining steroid hormones in transepithelial ion transport in a pluripotential epithelium. In surface cells of the colonic epithelium, basolateral KATP channels maintain the driving force for Na+ absorption. Aldosterone rapidly stimulates ATP-sensitive K+ (KATP) channels by inducing an intracellular alkalinization, thereby increasing the capacity for Na+ absorption. Basolateral Ca2+-sensitive K+ (KCa) channels in secretory cells at the base of the crypt generate charge balance during Cl– efflux. Estradiol rapidly inhibits Cl– secretion by downregulating KCa channels. PKC, protein kinase C.

	Cell signaling responses to aldosterone

Top Introduction Nongenomic targets of... Cell signaling responses to... Rapid nongenomic targets of... Cell signaling responses to... Common and divergent signaling... Conclusion References

 
Aldosterone directly stimulates the activity of PKC- in a cell-free assay system containing only purified commercially available enzyme, appropriate substrate peptide, cofactors, and lipid vesicles (3). Aldosterone did not stimulate the activity of the other PKC isoforms known to be present in distal colonic epithelium: PKC-, -, and - (2). In addition, aldosterone stimulates PKC-dependent Ca²⁺ entry through an L-type channel in rat and human distal colonic crypts (4, 5).

These results demonstrate a direct and specific interaction of aldosterone with the Ca²⁺-sensitive PKC isoform PKC-. Thus PKC- is a candidate nongenomic receptor for aldosterone (Fig. 3). There is also evidence that more than one receptor is involved in the nongenomic aldosterone response. Arachidonic acid release via the phospholipase A₂ pathway is also an important step in transducing rapid responses to aldosterone. Pretreatment with the G protein inhibitor pertussis toxin and the phospholipase A₂ antagonist quinacrine significantly inhibited aldosterone-induced stimulation of the Na⁺/H⁺ exchanger and K_ATP current in colonic cells. Inhibition of prostaglandin synthesis via the cyclooxygenase pathway abolished the stimulatory response to the steroid hormone. Conversely, inhibition of the lipoxygenase pathway did not prevent the increase in K_ATP channel activity or activation of the Na⁺/H⁺ exchanger induced by aldosterone (18). The results of these studies indicate that, in addition to PKC, there may be a role for membrane-associated signaling in the transduction of rapid steroid hormone responses on ion transport and pH_i regulation in pluripotential epithelia.

View larger version (23K): [in this window] [in a new window]   FIGURE 3. Common and divergent nongenomic signaling pathways for aldosterone and estradiol. Aldosterone binds directly to PKC-, which stimulates Ca2+ influx via L-type Ca2+ channels. The resulting increase in intracellular Ca2+ concentration ([Ca2+]i) amplifies the activity of the Ca2+-dependent PKC-, enabling upregulation of Na+/H+ exchange. This causes an intracellular alkalinization that stimulates basolateral KATP channels. Estradiol directly activates both PKC- and PKC-. PKC- stimulates adenylyl cyclase (AC), causing activation of protein kinase A (PKA), which phosphorylates L-type Ca2+ channels causing Ca2+ influx. The increased [Ca2+]i permits PKC-dependent upregulation of Na+/H+ exchange, and the subsequent increase in intracellular pH (pHi) inhibits KCa channel activity. The estradiol-induced PKC- signaling step (*) is absent in tissues of male origin.

	Rapid nongenomic targets of estradiol

Top Introduction Nongenomic targets of... Cell signaling responses to... Rapid nongenomic targets of... Cell signaling responses to... Common and divergent signaling... Conclusion References

A possible physiological function of estradiol may be to alter transepithelial ion transport. Plasma estrogen concentrations increase dramatically during gestation and in other high-estrogen states such as certain phases of the menstrual cycle and following use of the combined oral contraceptive pill. High estrogen states are associated with salt and water retention, resulting in edema and hypertension (cf. Ref. 3). This observation supports a role for estradiol in whole body salt and water homeostasis.

The transcellular movement of Cl^– drives the efflux of salt and water in many secretory epithelia. Basolateral K_Ca channels play an important role in this process, because blockade of these channels reduces both basal Cl^– secretion and Cl^– secretion prestimulated by secretagogues (10). Estradiol has been shown to rapidly inhibit basolateral K_Ca channel activity, which would be expected to result in an acute inhibition of Cl^– secretion (Fig. 2). Recently, we have shown that physiological concentrations of estradiol (0.1–10 nM) reduce both basal and secretagogue-induced Cl^– secretion (1). The antisecretory effect of estradiol is sensitive to PKC inhibition or intracellular Ca²⁺ chelation and is gender specific, occurring only in tissues of female origin. These observations link nongenomic second messengers with a rapid, gender-specific effect in the whole tissue. The nongenomic effect of estradiol to decrease Cl^– secretion occurs only in epithelia of female origin and may underlie the increased salt and water retention observed clinically in high-estrogen states.

	Cell signaling responses to estradiol

Top Introduction Nongenomic targets of... Cell signaling responses to... Rapid nongenomic targets of... Cell signaling responses to... Common and divergent signaling... Conclusion References

 
One of the earliest reports of rapid effects of 17ß-estradiol was made in 1969 by Szego and Davis (13). They showed that estrogen treatment of rats in vitro resulted in an acute elevation of cAMP in uterine smooth muscle. In female rat distal colon, estradiol produces rapid nongenomic effects on PKC and cAMP-dependent protein kinase (PKA) (3, 4). Fast effects on [Ca²⁺]_i are also observed via PKA- and PKC-sensitive pathways. These rapid signaling responses are sex-steroid selective, insensitive to estrogen receptor antagonists, and gender specific.

Because the only known physiological regulator of PKA is cAMP, the stimulatory effect of estradiol on PKA activity must be indirect since the nongenomic response is sensitive to adenylyl cyclase inhibition and is mimicked by forskolin. Also, the hormone does not cause a direct stimulation of PKA activity in either type I or type II commercially available PKA holoenzymes (3). The most obvious conclusion therefore is that estradiol stimulates adenylyl cyclase activity indirectly to produce the nongenomic effect on PKA.

It has previously been demonstrated (19) that certain isoforms of adenylyl cyclase are activated by PKC. Estradiol produces a rapid stimulation of PKC activity in rat distal colonic epithelium (4), and it is possible that the estradiol-stimulated PKA activity is mediated via this pathway. This conclusion is reinforced by the observation that specific PKC antagonists inhibit the estradiol-induced stimulation of PKA activity. In contrast, however, PKC inhibition has no inhibitory effect on cAMP-stimulated PKA activity. Estradiol stimulation of PKA involves an initial activation of PKC before upregulation of adenylyl cyclase activity (3). This effect is PKC isoform specific (Fig. 3).

Estradiol directly and specifically stimulates PKC- activity in a cell-free assay system. Other steroid hormones such as 17-estradiol, progesterone, testosterone, aldosterone, hydrocortisone, and dexamethasone are without effect on PKC- activity. Estradiol also activates PKC-. However, the involvement of this Ca²⁺- and phospholipid-dependent PKC isoform in the estradiol-induced stimulation of PKA activity can be ruled out. Both aldosterone and the stereoisomer 17-estradiol, which activate PKC-, have no stimulatory effect on PKA (3). We propose, therefore, that the cytosolic protein responsible for the rapid nongenomic PKA response to estradiol is the Ca²⁺-independent, phospholipid-dependent PKC- isoform. The PKC- isoform may be a nongenomic receptor for estradiol (Fig. 3).

	Common and divergent signaling pathways for rapid effects of aldosterone and estradiol

Top Introduction Nongenomic targets of... Cell signaling responses to... Rapid nongenomic targets of... Cell signaling responses to... Common and divergent signaling... Conclusion References

 
Aldosterone and estradiol differ in their protein kinase signal transduction, and both hormones stimulate specific PKC isoforms. Isozyme-specific properties such as substrate specificities, subcellular localization, activation requirements, and rates of downmodulation suggest that different PKC isoforms may perform unique cellular functions.

Initially, there appeared to be a common stimulatory signaling pathway for rapid nongenomic responses to aldosterone and estradiol, i.e., PKC. Our recent results (3) now suggest that these steroid hormones stimulate different PKC isozymes, with aldosterone stimulating PKC- selectively and estradiol stimulating both PKC- and PKC-. These results indicate both common and divergent signaling systems for salt-retaining steroid hormones. These properties could offer an explanation for common transporter targeting and yet confer gender specificity.

	Conclusion

Top Introduction Nongenomic targets of... Cell signaling responses to... Rapid nongenomic targets of... Cell signaling responses to... Common and divergent signaling... Conclusion References

 
Current evidence points to different PKC isoforms as nongenomic receptors for rapid responses to steroids (3, 12). The physiological function of nongenomic effects of aldosterone and estradiol is to shift the balance from net secretion to net absorption in a pluripotential epithelium.

	References

Top Introduction Nongenomic targets of... Cell signaling responses to... Rapid nongenomic targets of... Cell signaling responses to... Common and divergent signaling... Conclusion References

 

1. Condliffe SB, Doolan CM, and Harvey BJ. 17ß-oestradiol regulates Cl^– secretion in rat distal colonic epithelium. J Physiol (Lond) 30: 47–54, 2001.
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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (25) Citing Articles via Google Scholar Google Scholar Articles by Harvey, B. J. Articles by Doolan, C. M. Search for Related Content PubMed PubMed Citation Articles by Harvey, B. J. Articles by Doolan, C. M.