MinireviewThe digitalis-like steroid hormones: New mechanisms of action and biological significance
Introduction
Digitalis is a general term for steroidal drugs prepared from the seeds and dried leaves of the genus Digitalis, which are used as a cardiac stimulant. More than a quarter of a century has elapsed since the first demonstrations, at the cellular and molecular levels, of the presence of digitalis-like compounds (DLC) in mammalian tissues. The hundreds of scientific reports that have appeared since then unequivocally support the notion that these compounds function as hormones in mammals: They are synthesized and released from the adrenal gland and by interacting with their receptor, Na+, K+-ATPase, they affect numerous cellular functions. It is the purpose of this review to provide a broad overview of the structure and biosynthesis of these hormones, with a detailed discussion of their mechanisms of action and biological significance, as well as to delineate the open questions in this field.
Section snippets
Historical perspective
The medical use of digitalis steroids (cardiac glycosides), for more than 200 years, stemmed from an herbal remedy rather than from laboratory chemistry. The English physician William Withering is credited with discovering in 1775 that the foxglove plant could help those suffering from abnormal fluid buildup, or dropsy, as it was called in those days (Peck and Wilkinson, 1950). In 1930, Sydney Smith of Burroughs Wellcome isolated the steroid glycoside digoxin from Digitalis lanata and this
Identification of endogenous DLC
Digitalis compounds can be classified as cardenolides, compounds identified originally in plants, and bufadienolides, identified in toad venom. They share a common general structure: i.e. a steroid nucleus with a lactone ring at C-17 and a hydroxyl group at C-14. The 5-membered- and 6-membered-lactone rings, in cardenolides and bufadienolides, respectively, are considered the most essential functional group of these substances (Guntert and Linde, 1981). The endogenous DLC are either
DLC biosynthesis and release
Extensive data have shown that DLC are present at relatively high concentrations in the adrenal gland, that adrenalectomy leads to a drop in ouabain plasma levels (Masugi et al., 1988) and that the adrenal cortex synthesizes DLC (for previous review see Lichtstein and Rosen, 2001). Furthermore, the synthesis of DLC has also been demonstrated in tissue culture of primary adrenocortical cells (Komiyama et al., 2001, Perrin et al., 1997).
In all steroidogenic tissues, regardless of the hormones
The receptor — the Na+, K+-ATPase
DLC act by binding to a specific, extracellular receptor — the α subunit of the sodium, potassium-activated adenosine triphosphatase Na+, K+-ATPase (EC 3.6.1.37). This enzyme is an oligomer composed of three polypeptides, the α, β, and FXYD subunits (Fig. 2). Thus far, 4 α, 3 β and 7 FXYD isoform subunits (6 out of which are associated with the Na+, K+-ATPase) have been identified in human (Blanco and Mercer, 1998, Geering, 2006). The α subunit is a multispanning membrane protein that is
DLC mechanisms of action at the cellular and molecular levels
Multiple roles for a single protein are now a well accepted phenomenon. For example, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was considered a classical glycolytic protein studied mainly for its essential role in energy production. However, recent evidence shows that mammalian GAPDH displays a number of diverse activities unrelated to its glycolytic function. These include its role in membrane fusion, microtubule bundling, phosphotransferase activity, nuclear RNA export, DNA replication
DLC binding to plasma proteins and their degradation
The concentrations of hormone ligands in the circulation and at target sites are maintained through coordinated regulation of steroid biosynthesis and degradation. In most cases steroid hormones lose their receptor reactivity when they are bound to binding proteins, whereas metabolic conversion can result in active or inactive metabolites (You, 2004). Hydroxylation by cytochrome P450 (CYP) enzymes and conjugation with glucuronide and sulfate are among the major hepatic pathways of steroid
DLC systemic physiological roles and pathological implications
All the known hormones are multifunctional, exerting diverse functions in different tissues under various physiological conditions. In this respect DLC are not different and have already been implicated in the regulation of several major physiological parameters including water and salt homeostasis, cardiac contractility and rhythm, systemic blood pressure, cell growth and differentiation and behavior (Fig. 3). In many cases, perturbation of the DLC system has been implied in pathological
Conclusions
We have reviewed some aspects of a very large and expanding area of research on endogenous DLC. The work of recent years has demonstrated that cardenolide and bufadienolide DLC are present in animal tissues and that they are synthesized by the adrenal gland and presumably also in the brain. Recent work has elucidated many molecular consequences of the interaction of DLC with their receptor, Na+, K+-ATPase. The evidence for the involvement of DLC in hypertension, depressive disorders and cancer
Acknowledgment
This work was supported by Grant No. 269.04 from the Israel Science Foundation.
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