Chapter Five - Aldosterone and Ion Channels
Introduction
As early as the 1950s, aldosterone was shown to decrease the excretion of Na+ (Barger, Berlin, & Tulenko, 1958) and increase the excretion of K+ and H+ (Bartter, 1956). This foundational relationship between aldosterone and ion regulation has intimately tied aldosterone to ion channels. As expected of a steroid hormone, many of the ion channel mechanisms require aldosterone to freely enter cells (Porter, Bogoroch, & Edelman, 1964) and interact with the high affinity type 1 mineralocorticoid receptor (MR) (Funder, Feldman, & Edelman, 1973). From this interaction, aldosterone can modulate ion channels through genomic or non-genomic pathways. In genomic cascades, aldosterone/MR directly upregulates ion channel transcription and/or alters ion channel expression/function via the transcriptional upregulation of intermediary proteins. In the non-genomic cascades, aldosterone alters ion channel expression/function through non-transcriptional means. In this chapter, we review the literature focusing on ion channels regulated by aldosterone, while discussing the appropriate genomic and non-genomic pathways.
Section snippets
Sodium Channels
Na+ regulation is a principle homeostatic function of aldosterone. As described above, the earliest reported action of aldosterone involves Na+ excretion. In this feedback cycle, low plasma [Na+] induces aldosterone secretion (Deane, Shaw, & Greep, 1948) from the adrenal cortex (Giroud, Stachenko, & Venning, 1956), which in turn decreases Na+ excretion and therefore increases plasma [Na+]. It is now understood that aldosterone acts on Na+ transporters/channels in the distal tubule and colon to
Potassium Channels
K+ regulation is a second fundamental component of aldosterone homeostasis that dates back to the origin of electrolyte regulation by the hormone (Bartter, 1956). As with Na+, changes in plasma [K+] also act as a stimulus for aldosterone release. However, elevated plasma [K+] stimulates aldosterone secretion (Laragh & Stoerk, 1957), with downstream effects involving increased K+ secretion in the distal tubule via K+ channels.
Calcium Channels
Aldosterone and Ca2+ are uniquely linked as intracellular Ca2+ and voltage-gated Ca2+ channels regulate the production of aldosterone (Barrett et al., 2016); however, the impact of secreted aldosterone on Ca2+ channel targets remains less understood. Presently there are several ion channel candidates, including Transient Receptor Potential Vanilloid (TRPV) 4, 5, and 6, which may become more relevant as they are further explored.
TRPV4 is a non-selective cation channel (Voets et al., 2002;
Chloride Channels
Similar to Ca2+, the pathways connecting aldosterone to Cl− channels remain indirect and through secondary proteins. However, they are relevant in the aldosterone-sensitive distal nephron and worth briefly describing. To begin, Cl− transport through ion channels in the DCT is mediated by ClC-Kb(2)/barttin (Birkenhager et al., 2001; Kobayashi, Uchida, Mizutani, Sasaki, & Marumo, 2001) and the cystic fibrosis transmembrane conductance regulator (CFTR) (Rubera et al., 1999). While ClC-Kb/barttin
Conclusions and Future Directions
Classically thought to regulate Na+ and K+, the multitude of mechanisms by which aldosterone modulates Na+, K+, H+, Ca2+, Mg2+, and Cl− channels suggests that aldosterone has a broad physiological capacity to regulate ion homeostasis. This is clinically relevant because drugs that target aldosterone and the MR, such as spironolactone and eplerenone, are increasingly being used in the management hypertension, heart failure, arrhythmias and renal disease (Funder, 2010; Tam et al., 2017). While
Acknowledgments
Support was provided by Grants from the Canadian Institute of Health Research (CIHR—MOP57786) and (CIHR-MOP-133451). R.M.T. was supported through a Canada Research Chair/Canadian Foundation for Innovation award and British Heart Foundation Chair (CH/4/29762).
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2022, European Journal of PharmacologyCitation Excerpt :Aldosterone is an important mineralocorticoid, which when oversecreted promotes hypertension and heart failure (Gaddam et al., 2009). Since its discovery, aldosterone has been known as an ion channel regulator (Valinsky et al., 2019). Vasoactive substances including aldosterone were found to regulate TRPM7 mRNA and protein levels (He et al., 2005).
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2020, European Journal of Medicinal ChemistryCitation Excerpt :At the thick ascending loop of Henle, ROMK enables potassium recycling across the luminal membrane, a requirement for effective functioning of the furosemide-sensitive Na+/K+/2Cl- channel. Potassium efflux through ROMK augments the role of transporters and sodium channels, which are known targets of diuretics [79]. In recent years, understanding of the physiological role of ROMK has shown an intriguing pharmacological target for developing an innovative class of diuretic agents for the treatment of hypertension and HF: the ROMK inhibitors.
Hormonal Regulation of Epithelial Sodium Channel (ENaC) and Other Nonneuronal Epithelial Ion Channels
2020, Hormonal Signaling in Biology and Medicine: Comprehensive Modern EndocrinologyRegulation of ion channels in the microcirculation by mineralocorticoid receptor activation
2020, Current Topics in MembranesCitation Excerpt :The regulation of ENaC by aldosterone involves glucocorticoid-induced leucine zipper (GILZ) protein (Robert-Nicoud et al., 2001) and connector enhancer of kinase suppressor of ras-3 (CNK3) (Ziera et al., 2009). The precise molecular mechanisms though which aldosterone regulates ENaC expression have been eloquently described by Valinsky et al. (2019). Studies of the effects of aldosterone on ENaC expression have shown that aldosterone increases ENaC expression but that the cytoskeleton in the endothelial cells must be intact for this to occur (Golestaneh et al., 2001).
Hormonal Regulation of Epithelial Sodium Channel (ENaC) and Other Nonneuronal Epithelial Ion Channels
2019, Hormonal Signaling in Biology and Medicine: Comprehensive Modern Endocrinology