Cortisol resistance in the degu (Octodon degus)

Area of Science:

• Endocrinology
• Molecular Biology
• Comparative Physiology

Background:

• Cortisol resistance is observed in degus (Octodon degus), a New World hystricomorph.
• The degu is a model organism for stress, diurnal rhythms, and behavioral studies.
• Guinea pigs, another New World hystricomorph, also exhibit glucocorticoid resistance due to differing amino acid sequences in their glucocorticoid receptors (GR).

Purpose of the Study:

• To investigate if sequence variations in the degu GR ligand-binding domain (LBD) contribute to cortisol resistance.
• To compare the degu GR resistance mechanism with that of the guinea pig GR.

Main Methods:

• Cloning and expression of the degu GR LBD.
• Characterization of the degu GR LBD's interaction with cortisol.
• Comparative sequence analysis of degu and other mammalian GRs.

Main Results:

• The degu GR LBD was successfully cloned and expressed.
• Cortisol resistance in the degu GR is not due to the same amino acids or region responsible for resistance in the guinea pig GR.
• A novel mechanism for cortisol resistance was identified in the degu GR, involving the substitution of two conserved isoleucine residues with valine in the LBD.

Conclusions:

• The degu GR exhibits relative cortisol resistance attributed to a unique substitution of isoleucine with valine residues between helices 5 and 6 of the LBD.
• This finding elucidates a distinct molecular basis for glucocorticoid resistance in the degu, differing from the guinea pig model.
• The identified amino acid changes in the degu GR LBD provide insights into ligand-binding affinity regulation in steroid receptors.