Proton transfer from ligands activates extranuclear-initiated estrogen receptor signaling

Ligand binding to estrogen receptors (ER), ERα and ERβ, controls the physiology of estrogen-responsive tissues through nuclear and extranuclear initiated pathways. We have found that ligands activate the extranuclear pathway by a mechanism involving proton transfer. The low affinity ligand and widespread endocrine disruptor Bisphenol-A (BPA) initiated nuclear and extranuclear actions. Concentrations similar to the receptor affinity initiated the nuclear pathway, whereas much lower concentrations initiated the extranuclear pathway. Experiments in different cell types using deuterated molecules of BPA and the ERβ agonist, diarylpropionitrile (DPN), indicated that a proton transfer from the hydroxyl groups to an amino acid acceptor within the ligand binding domain switches the extranuclear pathway. Activation of this pathway elicited a pattern of protein interactions with ERβ that regulated most of the important cellular functions. Thus, the extranuclear actions of ERβ are initiated by a molecular mechanism different from that of nuclear actions. This mechanism may work for other ligands and nuclear receptors. ### Competing Interest Statement The authors have declared no competing interest.