11-Deoxycortisol is a corticosteroid hormone in the lamprey

Abstract

Corticosteroid hormones are critical for controlling metabolism, hydromineral balance, and the stress response in vertebrates. Although corticosteroid hormones have been well characterized in most vertebrate groups, the identity of the earliest vertebrate corticosteroid hormone has remained elusive. Here we provide evidence that 11-deoxycortisol is the corticosteroid hormone in the lamprey, a member of the agnathans that evolved more than 500 million years ago. We used RIA, HPLC, and mass spectrometry analysis to determine that 11-deoxycortisol is the active corticosteroid present in lamprey plasma. We also characterized an 11-deoxycortisol receptor extracted from sea lamprey gill cytosol. The receptor was highly specific for 11-deoxycortisol and exhibited corticosteroid binding characteristics, including DNA binding. Furthermore, we observed that 11-deoxycortisol was regulated by the hypothalamus-pituitary axis and responded to acute stress. 11-Deoxycortisol implants reduced sex steroid concentrations and upregulated gill Na + , K + -ATPase, an enzyme critical for ion balance. We show here that 11-deoxycortisol functioned as both a glucocorticoid and a mineralocorticoid in the lamprey. Our findings indicate that a complex and highly specific corticosteroid signaling pathway evolved at least 500 million years ago with the arrival of the earliest vertebrate.evolution | nuclear-receptor | stress response C orticosteroid hormones in vertebrates are critical for metabolism, growth, reproduction, immunity, and ion homeostasis, and are an important part of the coping mechanisms involved in the stress responses (1). Corticosteroids primarily act by binding to cytosolic receptors, which are then transported to the nucleus, where they act as positive and negative transcription factors (2). Their activity leads to the expression or repression of various regulatory proteins that counteract the effects of external stressors, thus maintaining homeostasis (2).The actions of corticosteroids appear to be conserved. Most vertebrates that have been examined share a stress response that includes increased glucocorticoid (GC) hormones that further regulate metabolic, endocrine, and immune functions. However, active hormones may differ among species. In tetrapod groups, there are at least two active GC hormones, either cortisol or corticosterone, and the mineralocorticoid (MC) that regulates ion balance is aldosterone. In contrast, in teleosts, cortisol apparently acts as both GC and MC, whereas aldosterone is not present (3). However, the corticosteroid signaling pathway in the earliest vertebrate has remained elusive because of lack of information on the identities of corticosteroids.Recent work with receptors has shed light on the primitive corticosteroid of vertebrates. A single putative corticosteroid receptor (CR) was identified through PCR-based homology cloning in the sea lamprey, a member of the oldest vertebrate lineages from which jawed vertebrates diverged about 500 million years ago (4, 5). Transactivation studies using...

Lamprey endocrinology is not ancestral

“…The ancestral receptor's promiscuity is strongly corroborated by the fact that lamprey and hagfish CRs, like the GRs and MRs of elasmobranchs, are all activated by both mineralocorticoids and glucocorticoids (2,5). The experiments of Close et al (1), interesting as they are, do not refute direct evidence of a broad-specificity ancestral CR. …”

“…The first concerns the specific biological activity of the P. marinus corticosteroid receptor (PmCR), the co-ortholog in lamprey of jawed vertebrates' glucocorticoid and mineralocorticoid receptors (GR and MR). Close et al (1) claimed that PmCR is endogenously and uniquely activated by S. This claim overreaches their finding that the cytosolic fraction of homogenated gill tissue binds S with higher affinity than other corticosteroids. P. marinus expresses not only CR but also another closely related steroid receptor (2); in addition, membrane receptors, enzymes, and other molecules with the potential to bind steroids may also be present (3).…”

“…The report of Close et al (1) in PNAS concerning corticosteroid signaling in the lamprey Petromyzon marinus elucidates interesting issues in comparative endocrinology. It does not, however, support the authors' claim that the ancestral corticosteroid receptor was specifically activated by the glucocorticoid 11-deoxycortisol (S) and that sensitivity to mineralocorticoids and other corticosteroids is evolutionarily derived.…”

“…Close et al (1) claimed that the ancestral CR-the ancient precursor of modern CRs, GR, and MRs-was activated by S and not other corticosteroids, on the basis of the contention that lamprey are "the closest living relative of the earliest vertebrate." This statement represents a conceptual error.…”

“…Close et al (1) reported that lamprey produce S and deoxycorticosterone (DOC) when treated with pituitary hormones; exogenous S triggers vertebrate-like mineralocorticoid and glucocorticoid responses. These data suggest that S, DOC, or their metabolites function in lamprey in a vertebrate-like endocrinological axis.…”