Glucocorticoid Receptor and SUMO Fluctuations in Response to Pulsatile Glucocorticoids In Vitro and in Male Rat Brains

We present a molecular mechanism underpinning how pulsatile patterns of glucocorticoid hormones maintain signal responsivity, evade hormone resistance, and promote homeostasis. Endogenous glucocorticoids are released in a pulsatile manner resulting in oscillating hormone signals with intermittent peaks of high glucocorticoids and troughs of low glucocorticoids. We show that ligand activation of glucocorticoid receptors rapidly triggers the post-translational modification SUMOylation, which is coupled to receptor degradation, whereby resistance to subsequent signal transduction is generated and ligand response attenuated. We find rapid, transient glucocorticoid receptor SUMOylation tracks ultradian (roughly hourly) pulse dynamics in cells, as well as circadian (daily) oscillatory rhythms in vivo, enabling cellular interpretation of fluctuating hormone patterns. Prolonged treatment with the long-acting synthetic glucocorticoid methylprednisolone disrupted glucocorticoid receptor SUMOylation levels in rat brain tissue. Pharmacological glucocorticoid therapy generates unremitting glucocorticoid signaling, which may substantially reduce the glucocorticoid receptor pool and contribute to the therapeutic problem of acquired glucocorticoid resistance. The physiological solution for maintaining signal responsivity over time is pulsatile hormone exposure, with pulsatile low glucocorticoid troughs which periodically limit receptor degradation and associated signal attenuation. We show low glucocorticoid periods allow time for depleted glucocorticoid receptor expression levels to recover and thereby maintain signal sensitivity. Our results reveal a molecular mechanism responsive to hormone pattern information, through which endogenous ultradian and circadian glucocorticoid fluctuations maintain glucocorticoid receptor expression and glucocorticoid sensitivity. Dynamic ligand-activated glucocorticoid receptor SUMOylation coupled to degradation is revealed as a component of glucocorticoid receptor protein regulation, whose expression is critical for metabolic, immunological, cognitive, and cardiovascular homeostasis.