Aldosterone and Dexamethasone Activate African Lungfish Mineralocorticoid Receptor: Increased Activation After Removal of the Amino-Terminal Domain

TL;DR

This study reveals that in African lungfish, aldosterone and certain corticosteroids activate the mineralocorticoid receptor, which is more strongly activated by truncated forms and may also function as a glucocorticoid receptor.

Contribution

It demonstrates that lungfish MR is activated by multiple corticosteroids, and that removal of the N-terminal domain enhances activation, suggesting a repressive role unlike in humans.

Findings

Aldosterone and specific corticosteroids have low EC50s, indicating high potency.

Truncated lungfish MR shows increased activation, implying N-terminal domain repression.

Dexamethasone and triamcinolone strongly activate lungfish MR, suggesting it may also act as a glucocorticoid receptor.

Abstract

Aldosterone, the main physiological mineralocorticoid in humans and other terrestrial vertebrates, first appears in lungfish, which are lobe-finned fish that are forerunners of terrestrial vertebrates. Aldosterone activation of the MR regulates internal homeostasis of water, sodium and potassium, which was critical in the conquest of land by vertebrates. We studied transcriptional activation of the slender African lungfish MR by aldosterone, other corticosteroids and progesterone and find that aldosterone, 11-deoxycorticosterone, 11-deoxycortisol and progesterone have half-maximal responses (EC50s) below 1 nM and are potential physiological mineralocorticoids. In contrast, EC50s for corticosterone and cortisol were 23 nM and 66 nM, respectively. Unexpectedly, truncated lungfish MR, consisting of the DNA-binding, hinge and steroid-binding domains, had a stronger response to corticosteroids and progesterone than full-length lungfish MR, indicating that the N-terminal domain represses steroid activation of lungfish MR, unlike human MR in which the N-terminal domain contains an activation function. BLAST searches of GenBank did not retrieve a GR ortholog, leading us to test dexamethasone and triamcinolone for activation of lungfish MR. At 10 nM, both synthetic glucocorticoids are about 4-fold stronger than 10 nM aldosterone in activating full-length lungfish MR, leading us to propose that lungfish MR also functions as a GR.