Elsevier

Vitamins and Hormones

Volume 109, 2019, Pages 105-131
Vitamins and Hormones

Chapter Five - Aldosterone and Ion Channels

https://doi.org/10.1016/bs.vh.2018.10.004Get rights and content

Abstract

Since its discovery, aldosterone and ion modulation have been entwined. While scientific investigations throughout the decades have emphasized aldosterone's connection to Na+, K+, and H+ homeostasis, more recent research has demonstrated a relationship between aldosterone and Mg2+, Ca2+, and Cl homeostasis. The mechanisms connecting aldosterone to ion regulation frequently involve ion channels; the membrane localized proteins containing at least one aqueous pore for ion conduction. In order to precisely control intracellular or intraorganelle ion concentrations, ion channels have evolved highly specific regions within the conduction pore that select ions by charge, size, and/or dehydration energy requirement, meaning aldosterone must be able to modulate multiple ion channels to regulate the many ions described above. The list of ion channels presently connected to aldosterone includes ENaC (Na+), ROMK/BK (K+), TRPV4/5/6 (Ca2+), TRPM7/6 (Mg2+), and ClC-K/CFTR (Cl), among others. This list is only expected to grow over time, as the promiscuity of aldosterone becomes more understood.

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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