ArticleProceedings of the National Academy of Sciences of the United States of America2014
Mutation of the palmitoylation site of estrogen receptor α in vivo reveals tissue-specific roles for membrane versus nuclear actions.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 143 papers.
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Who cites it
143 citing papers in PubMed, 246 citations in OpenAlex.
- Unique effects on hepatic function, lipid metabolism, bone and growth endocrine parameters of estetrol in combined oral contraceptives.The European journal of contraception & reproductive health care : the official journal of the European Society of Contraception · 2015Trial
- Inhibition of ovulation by administration of estetrol in combination with drospirenone or levonorgestrel: Results of a phase II dose-finding pilot study.The European journal of contraception & reproductive health care : the official journal of the European Society of Contraception · 2015Trial
- Hypothalamic actions of estrogens in the regulation of energy and glucose homeostasis.Reviews in endocrine & metabolic disorders · 2026Review
- CTHRC1-driven breast cancer progression: insights from palmitoylation networks and spatial heterogeneity.BMC cancer · 2025Article
- Membrane-initiated estrogen receptor-α signaling in osteoblasts is crucial for normal regulation of the cortical bone in female mice.Bone research · 2025Article
- Altered thermal preference by preoptic estrogen receptor alpha neurons in postpartum females.Molecular metabolism · 2025Article
- Endothelial oestrogen-myocardial cyclic guanosine monophosphate axis critically determines angiogenesis and cardiac performance during pressure overload.Cardiovascular research · 2024Article
- Impact of hormonal contraception on endometrial histology in patients with Lynch syndrome, a retrospective pilot study.Familial cancer · 2024Article
- Identification of an ionic mechanism for ERα-mediated rapid excitation in neurons.Science advances · 2024Article
- Role of Membrane Estrogen Receptor Alpha on the Positive Feedback of Estrogens on Kisspeptin and GnRH Neurons.eNeuro · 2024Article
- Unraveling the Dynamics of Estrogen and Progesterone Signaling in the Endometrium: An Overview.Cells · 2024Review
- Role for Nongenomic Estrogen Signaling in Male Fertility.Endocrinology · 2024Article
- Reprogramming of endothelial gene expression by tamoxifen inhibits angiogenesis and ERα-negative tumor growth.Theranostics · 2024Article
- Review
- Stress-related cellular pathophysiology as a crosstalk risk factor for neurocognitive and psychiatric disorders.BMC neuroscience · 2023Review
- Increased palmitoylation improves estrogen receptor alpha-dependent hippocampal synaptic deficits in a mouse model of synucleinopathy.Science advances · 2023Article
- International Union of Basic and Clinical Pharmacology CXIII: Nuclear Receptor Superfamily-Update 2023.Pharmacological reviews · 2023Review
- Estrogen receptor alpha mediates 17β-estradiol, up-regulates autophagy and alleviates hydrogen peroxide-induced vascular senescence.Biogerontology · 2023Article
- URAT1 is expressed in cardiomyocytes and dotinurad attenuates the development of diet-induced metabolic heart disease.iScience · 2023Article
- TRIM28 modulates nuclear receptor signaling to regulate uterine function.Nature communications · 2023Article
83 more citing papers are in PubMed but not listed here.
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Authors and funding
20 authors at 7 institutions in 2 countries.
Funding
Abstract
Estrogen receptor alpha (ERα) activation functions AF-1 and AF-2 classically mediate gene transcription in response to estradiol (E2). A fraction of ERα is targeted to plasma membrane and elicits membrane-initiated steroid signaling (MISS), but the physiological roles of MISS in vivo are poorly understood. We therefore generated a mouse with a point mutation of the palmitoylation site of ERα (C451A-ERα) to obtain membrane-specific loss of function of ERα. The abrogation of membrane localization of ERα in vivo was confirmed in primary hepatocytes, and it resulted in female infertility with abnormal ovaries lacking corpora lutea and increase in luteinizing hormone levels. In contrast, E2 action in the uterus was preserved in C451A-ERα mice and endometrial epithelial proliferation was similar to wild type. However, E2 vascular actions such as rapid dilatation, acceleration of endothelial repair, and endothelial NO synthase phosphorylation were abrogated in C451A-ERα mice. A complementary mutant mouse lacking the transactivation function AF-2 of ERα (ERα-AF2(0)) provided selective loss of function of nuclear ERα actions. In ERα-AF2(0), the acceleration of endothelial repair in response to estrogen-dendrimer conjugate, which is a membrane-selective ER ligand, was unaltered, demonstrating integrity of MISS actions. In genome-wide analysis of uterine gene expression, the vast majority of E2-dependent gene regulation was abrogated in ERα-AF2(0), whereas in C451A-ERα it was nearly fully preserved, indicating that membrane-to-nuclear receptor cross-talk in vivo is modest in the uterus. Thus, this work genetically segregated membrane versus nuclear actions of a steroid hormone receptor and demonstrated their in vivo tissue-specific roles.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.