ANTIDEPRESSANTS INHIBIT FKBP51 REGULATION OF THE GLUCOCORTICOID RECEPTOR ACTIVITY

BUDZIÑSKI, MAIA LUDMILA*; SENIN, SERGIO; REIN, THEO; LIBERMAN, ANA#; UGO, BELÉN; SCHMIDT, MATHIAS; BINDER, ELISABETH; GOBBINI, ROMINA*; SOKN, CLARA*; GASSEN, NILS; ARZT, EDUARDO#

Ciudad Autónoma de Buenos Aires

Congreso; LXVI Reunión Científica Anual de la Sociedad Argentina de Investigación Clínica (SAIC); 2021

Sociedad Argentina de Investigación Clínica

Glucocorticoids are the main effectors of the hypothalamic-pituitary-adrenal axis and key mediators of the stress response. They exert their function by binding to the glucocorticoid receptor (GR), which in turn translocates to the nucleus and modulates gene transcription. FK506-binding protein 51 (FKBP51) is an Hsp90 co-chaperone that tightly regulates the activity of the GR. Abnormal FKBP51 function has been associated to stress-related disorders and to antidepressant (AD) treatment response. Our group has demonstrated the key role of FKBP51 SUMO conjugation in the regulation of Hsp90-mediated inhibitory effect on GR activity. Our data shows that ADs, particularly clomipramine, inhibit FKBP51 SUMOylation by inhibiting its interaction with the SUMO E3 ligase PIAS4. The inhibition of FKBP51 SUMOylation by these drugs diminishes the formation of the inhibitory complex between FKBP51, Hsp90 and GR. To confirm the importance of PIAS4 in this context we performed co-immunoprecipitation assays between FKBP51 and Hsp90 in the presence of clomipramine and increasing amounts of PIAS4. We observed that PIAS4 over-expression dose dependently dampens the inhibitory effect of clomipramine on FKBP51 and Hsp90 interaction (53,6±16,7%; p