The role of membrane ERα signaling in bone and other major estrogen responsive tissues

• Published in: Scientific reports Vol. 6; no. 1; p. 29473
• Main Authors: Gustafsson, K. L., Farman, H., Henning, P., Lionikaite, V., Movérare-Skrtic, S., Wu, J., Ryberg, H., Koskela, A., Gustafsson, J.-Å., Tuukkanen, J., Levin, E. R., Ohlsson, C., Lagerquist, M. K.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 08.07.2016; Nature Publishing Group
• Subjects: 38/77; 631/80/86/2363; 64/110; 692/308/2778; Adipose Tissue - drug effects; Animals; beta; Cell Membrane - genetics; Cell Membrane - metabolism; Clinical Medicine; Endocrinology and Diabetes; Endokrinologi och diabetes; Estradiol - pharmacology; Estrogen Receptor alpha - genetics; Estrogen Receptor alpha - metabolism; extranuclear; Feedback, Physiological; Female; growth; health; Humanities and Social Sciences; Humerus - metabolism; Klinisk medicin; Lipoylation; Liver - metabolism; localization; Mice; multidisciplinary; Mutation; nuclear; Organ Size - drug effects; Organ Specificity; Ovariectomy; profile; receptor-alpha; Science; Science & Technology - Other Topics; Signal Transduction; Thymus Gland - metabolism; update; Uterus - metabolism
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep29473

Estrogen receptor α (ERα) signaling leads to cellular responses in several tissues and in addition to nuclear ERα-mediated effects, membrane ERα (mERα) signaling may be of importance. To elucidate the significance, in vivo , of mERα signaling in multiple estrogen-responsive tissues, we have used female mice lacking the ability to localize ERα to the membrane due to a point mutation in the palmitoylation site (C451A), so called Nuclear-Only-ER (NOER) mice. Interestingly, the role of mERα signaling for the estrogen response was highly tissue-dependent, with trabecular bone in the axial skeleton being strongly dependent (>80% reduction in estrogen response in NOER mice), cortical and trabecular bone in long bones, as well as uterus and thymus being partly dependent (40–70% reduction in estrogen response in NOER mice) and effects on liver weight and total body fat mass being essentially independent of mERα (<35% reduction in estrogen response in NOER mice). In conclusion, mERα signaling is important for the estrogenic response in female mice in a tissue-dependent manner. Increased knowledge regarding membrane initiated ERα actions may provide means to develop new selective estrogen receptor modulators with improved profiles.