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

Journal article
Authors Karin L. Gustafsson
Helen H. Farman
Petra Henning
Vikte Lionikaite
Sofia Movérare-Skrtic
Jianyao Wu
Henrik Ryberg
A. Koskela
J. A. Gustafsson
J. Tuukkanen
E. R. Levin
Claes Ohlsson
Marie K Lagerquist
Published in Scientific Reports
Volume 6
Pages Article number: 29473
ISSN 2045-2322
Publication year 2016
Published at Centre for Bone and Arthritis Research
Institute of Medicine, Department of Internal Medicine and Clinical Nutrition
Pages Article number: 29473
Language en
Keywords receptor-alpha, mice, nuclear, extranuclear, beta, localization, profile, update, health, growth, Science & Technology - Other Topics
Subject categories Endocrinology, Clinical Medicine


Estrogen receptor a (ER alpha) signaling leads to cellular responses in several tissues and in addition to nuclear ER alpha-mediated effects, membrane ER alpha (mER alpha) signaling may be of importance. To elucidate the significance, in vivo, of mER alpha signaling in multiple estrogen-responsive tissues, we have used female mice lacking the ability to localize ER alpha to the membrane due to a point mutation in the palmitoylation site (C451A), so called Nuclear-Only-ER (NOER) mice. Interestingly, the role of mER alpha 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 mER alpha (<35% reduction in estrogen response in NOER mice). In conclusion, mER alpha signaling is important for the estrogenic response in female mice in a tissue-dependent manner. Increased knowledge regarding membrane initiated ER alpha actions may provide means to develop new selective estrogen receptor modulators with improved profiles.

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