Deconstructing the Glucocorticoid Receptor: Pharmacological Implications

DIEGO M PRESMAN

Mar del Plata

Congreso; Congreso de la Sociedad Argentina de Biología; 2019

Sociedad Argentina de Biología (SAB)

Synthetic glucocorticoids (GCs) are one of the most prescribed pharmaceuticals world-wide due to their powerful anti-inflammatory and immunosuppressive activities. The action of GCs is mediated by the glucocorticoid receptor (GR), a member of the nuclear receptor superfamily of transcription factors. The GR is involved in many physiological processes, including the regulation of cell death and proliferation. Historically, GR transcriptional activity and clinical outcomes have been linked to its dimeric/monomeric state. A widely discussed model suggests that dimeric GR regulates unfavorable metabolic pathways, while monomeric GR is responsible for anti-inflammatory activities. Hence, GR ligands that preferentially induce the monomeric rather than the dimeric pathway should retain the desired pharmacological effects but will lack the undesired adverse reactions. However, the search for improved ligands under this paradigm has produced no significant results for the last 25 years. During this talk, I will present evidence against this predominant "dissociated model". By combining advance quantitative fluorescence microscopy techniques with genomic analysis on oligomeric mutant receptors, I will propose a new relationship between GR?s quaternary structure, chromatin binding and transcriptional output. This has important implications for the therapeutic uses of steroid hormones and the goal of finding selective anti-inflammatory drugs that do not create unwanted side-effects.