Molecular determinants of hormone sensitivity in rainbow trout glucocorticoid receptors 1 and 2

Armin Sturm (1, 2) , Louise Colliar (1) , Michael Leaver (1) , Nic R. Bury (2)

1 Institute of Aquaculture
2 Nutritional Sciences Division

Many teleost fish possess two glucocorticoid receptors (GR). In the rainbow trout rtGR1 and rtGR2 differ in their affinities to dexamethasone and EC50 values for glucocorticoids in transactivation assays, with rtGR2 being more sensitive. The objective of this study was to identify the molecular traits underlying the sensitivity difference. Domain-swap mutants between rtGR1 and rtGR2 showed that sensitivity was mainly determined by the hormone binding domain (E-domain). Chimeras exchanging three E-domain subregions indicated that all subregions influenced sensitivity, with the most C-terminal region that included AF2 having the greatest (12.6-fold) effects on cortisol transactivation EC50. The C-terminal extremity (CTE) in rtGR1 departs from a consensus preserved in other GRs. Introducing the consensus CTE into rtGR1 provoked a 4.2-fold decrease in transactivation EC50, suggesting CTE is one of several determinants of rtGR1's hyposensitivity. GRs with similar unusual CTEs exist in other salmonids, suggesting hyposensitive GR have evolved in this highly successful teleost lineage.

Mots clés: Steroid receptors; Teleost Fish; Cortisol; Stress response; Activation Function 2; ligand binding domain

Domaines: Biochimie, Biologie Moléculaire

Armin Sturm, Louise Colliar, Michael Leaver, Nic R. Bury. Molecular determinants of hormone sensitivity in rainbow trout glucocorticoid receptors 1 and 2. Molecular and Cellular Endocrinology, 2011, 333 (2), pp.181. ⟨10.1016/j.mce.2010.12.033⟩. ⟨hal-00668059⟩