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The rapid decline of circulating 17β-estradiol (E2) at menopause leads to negative neurological consequences, although hormone therapy paradoxically has both harmful and positive effects depending on the age at which it is delivered. The inconsistent response to E2 suggests unappreciated regulatory mechanisms for estrogen receptors (ERs), and we predicted it could be due to age-related differences in ERβ phosphorylation. We assessed ERβ phosphorylation using a sensitive mass spectrometry approach that provides absolute quantification (AQUA-MS) of individually phosphorylated residues. Specifically, we quantified phosphorylated ERβ in the hippocampus of women (aged 21-83 years) and in a rat model of menopause at 4 residues with conserved sequence homology between the 2 species: S105, S176, S200, and Y488. Phosphorylation at these sites, which spanned all domains of ERβ, were remarkably consistent between the 2 species, showing high levels of S105 phosphorylation (80%-100%) and low levels of S200 (20%-40%). Further, S200 phosphorylation decreased with aging in humans and loss of E2 in rats. Surprisingly, Y488 phosphorylation, which has been linked to ERβ ligand-independent actions, exhibited approximately 70% phosphorylation, unaltered by species, age, or E2, suggesting ERβ’s primary mode of action may not require E2 binding. We further show phosphorylation at 2 sites directly altered ERβ DNA-binding efficiency, and thus could affect its transcription factor activity. These findings provide the first absolute quantification of ERβ phosphorylation in the human and rat brain, novel insights into ERβ regulation, and a critical foundation for providing more targeted therapeutic options for menopause in the future.

Absolute Quantification of Phosphorylated ERβ Amino Acids in the Hippocampus of Women and in A Rat Model of Menopause