11-Deoxycortisol controls hydromineral balance in the most basal osmoregulating vertebrate, sea lamprey (Petromyzon marinus)

Abstract

It is unknown whether and how osmoregulation is controlled by corticosteroid signaling in the phylogenetically basal vertebrate group Agnatha, including lampreys and hagfishes. It is known that a truncated steroid biosynthetic pathway in lampreys produces two predominant circulating corticosteroids, 11-deoxycortisol (S) and 11-deoxycorticosterone (DOC). Furthermore, lampreys express only a single, ancestral corticosteroid receptor (CR). Whether S and/or DOC interact with the CR to control osmoregulation in lampreys is still unknown. We examined the role of the endogenous corticosteroids in vivo and ex vivo in sea lamprey (Petromyzon marinus) during the critical metamorphic period during which sea lamprey increase osmoregulatory capacity and acquire seawater (SW) tolerance. We demonstrate in vivo that increases in circulating [S] and gill CR abundance are associated with increases in osmoregulatory capacity during metamorphosis. We further show that in vivo and ex vivo treatment with S increases activity and expression of gill active ion transporters and improves SW tolerance, and that only S (and not DOC) has regulatory control over active ion transport in the gills. Lastly, we show that the lamprey CR expresses an ancestral, spironolactone-as-agonist structural motif and that spironolactone treatment in vivo increases osmoregulatory capacity. Together, these results demonstrate that S is an osmoregulatory hormone in lamprey and that receptor-mediated discriminative corticosteroid regulation of hydromineral balance is an evolutionarily basal trait among vertebrates. Corticosteroid signaling is central in controlling many physiological functions in vertebrates including metabolism, ion homeostasis and the stress response. Although the role of corticosteroids in controlling physiological function has been described in most vertebrate groups, the physiological role of corticosteroids and their receptor(s) in the phylogenetically basal vertebrate group Agnatha, represented by extant lamprey and hagfish, is not well understood. Recent investigations indicate that the terminal corticosteroids cortisol (F) and aldosterone (A) are absent in lamprey serum, whereas 11-deoxycortisol (S) and 11-deoxycorticosterone (DOC), respective steroid biosynthetic precursors to F and A in more derived vertebrates, are present at physiologically relevant levels 1-3. Still, it remains unclear whether the Agnathan corticosteroid receptor (CR), which is understood to be ancestral to the appearance and divergence of the mineralocorticoid (MR) and glucocorticoid (GR) receptors of later vertebrates 4 , has affinity for and is activated by S, DOC or both. For instance, one approach using classical ex vivo receptor binding studies demonstrated that the lamprey CR only had affinity for S 1 , yet a different approach expressing the ligand binding domain of the lamprey CR in mammalian cells in vitro demonstrated the lamprey CR can be activated by several corticosteroids including both endogenous terminal corticosteroids in lamprey, S and DOC 2. Thi...

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