RESUMEN
Psychedelics produce fast and persistent antidepressant effects and induce neuroplasticity resembling the effects of clinically approved antidepressants. We recently reported that pharmacologically diverse antidepressants, including fluoxetine and ketamine, act by binding to TrkB, the receptor for BDNF. Here we show that lysergic acid diethylamide (LSD) and psilocin directly bind to TrkB with affinities 1,000-fold higher than those for other antidepressants, and that psychedelics and antidepressants bind to distinct but partially overlapping sites within the transmembrane domain of TrkB dimers. The effects of psychedelics on neurotrophic signaling, plasticity and antidepressant-like behavior in mice depend on TrkB binding and promotion of endogenous BDNF signaling but are independent of serotonin 2A receptor (5-HT2A) activation, whereas LSD-induced head twitching is dependent on 5-HT2A and independent of TrkB binding. Our data confirm TrkB as a common primary target for antidepressants and suggest that high-affinity TrkB positive allosteric modulators lacking 5-HT2A activity may retain the antidepressant potential of psychedelics without hallucinogenic effects.
Asunto(s)
Antidepresivos , Alucinógenos , Dietilamida del Ácido Lisérgico , Psilocibina , Receptor trkB , Alucinógenos/metabolismo , Humanos , Células HEK293 , Sitios de Unión , Simulación de Dinámica Molecular , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Transducción de Señal , Receptor trkB/metabolismo , Plasticidad Neuronal/efectos de los fármacos , Antidepresivos/metabolismo , Regulación Alostérica , Masculino , Femenino , Animales , Ratones , Ratones Endogámicos C57BL , Embrión de Mamíferos/citología , Neuronas/efectos de los fármacos , Dietilamida del Ácido Lisérgico/química , Dietilamida del Ácido Lisérgico/metabolismo , Dietilamida del Ácido Lisérgico/farmacología , Psilocibina/química , Psilocibina/metabolismo , Psilocibina/farmacologíaRESUMEN
Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER)-located protein with cytoprotective effects in neurons and pancreatic ß cells in vitro and in models of neurodegeneration and diabetes in vivo. However, the exact mode of MANF action has remained elusive. Here, we show that MANF directly interacts with the ER transmembrane unfolded protein response (UPR) sensor IRE1α, and we identify the binding interface between MANF and IRE1α. The expression of wild-type MANF, but not its IRE1α binding-deficient mutant, attenuates UPR signaling by decreasing IRE1α oligomerization; phosphorylation; splicing of Xbp1, Atf6, and Txnip levels; and protecting neurons from ER stress-induced death. MANF-IRE1α interaction and not MANF-BiP interaction is crucial for MANF pro-survival activity in neurons in vitro and is required to protect dopamine neurons in an animal model of Parkinson's disease. Our data show IRE1α as an intracellular receptor for MANF and regulator of neuronal survival.