A transmembrane intracellular estrogen receptor mediates rapid cell signaling
Abstract
The steroid hormone estrogen regulates many functionally unrelated processes in numerous tissues. Although it is traditionally thought to control transcriptional activation through the classical nuclear estrogen receptors, it also initiates many rapid nongenomic signaling events. We found that of all G protein-coupled receptors characterized to date, GPR30 is uniquely localized to the endoplasmic reticulum, where it specifically binds estrogen and fluorescent estrogen derivatives. Activating GPR30 by estrogen resulted in intracellular calcium mobilization and synthesis of phosphatidylinositol 3,4,5-trisphosphate in the nucleus. Thus, GPR30 represents an intracellular transmembrane estrogen receptor that may contribute to normal estrogen physiology as well as pathophysiology.
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The biological effects of estrogen are mainly mediated via nuclear and membrane estrogen receptors (ERα, ERβ, and GPER), all three of which bind 17β-estradiol with high affinity in the low nM range.
“The biological effects of estrogen are mainly mediated via nuclear and membrane estrogen receptors (ERs), including estrogen receptor α (ERα), estrogen receptor β (ERβ), and G-protein-coupled ER (GPR30 or GPER), all three bind 17β-estradiol with high affinity in the low nM range (118, 119).”
From From mitochondria to sarcopenia: role of 17β-estradiol and testosterone (2023) · cites this paper as [119]
GPR30, renamed GPER1, transmits estrogen signals from the membrane.
“The estrogen receptor GPCR (GPR30) [23], which transmits estrogen signals from the membrane [24], has been renamed as G protein-coupled estrogen receptor 1 (GPER1) [25].”
From G protein-coupled receptors function as cell membrane receptors for the steroid hormone 20-hydroxyecdysone (2020) · cites this paper as [23]
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References 24 · Cited by 2,302
- Authors
- Revankar, C. M., Cimino, D. F., Sklar, L. A., Arterburn, J. B., & Prossnitz, E. R.
- Affiliations
- New Mexico State University (US)
- Corresponding author
- Prossnitz, Eric R.
- Venue
- Science
- Published
- 2005-03-11
- Volume
- 307
- Issue
- 5715
- Pages
- 1625-1630
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W1981467972
- Cited by
- 2,302
- References
- 24
- Citations by year
- 2026: 47 · 2025: 69 · 2024: 72 · 2023: 77 · 2022: 87 · 2021: 111 · 2020: 121 · 2019: 121 · 2018: 115 · 2017: 120 · 2016: 116 · 2015: 112 · 2014: 133 · 2013: 142 · 2012: 122
- FWCI
- 66.03
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (1s10rr014668-01, 5p20rr011830-03)
- National Cancer Institute (R24CA088339, R24CA88339)
- National Institute of Allergy and Infectious Diseases (AI36357)
- National Institute of Biomedical Imaging and Bioengineering (R24EB000264, EB 00264)
- National Center for Research Resources (P20 RR 11830, 1-S10-RR-14668)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Effects and risks of endocrine disrupting chemicals
- Keywords
- GPR30, estrogen receptor, non-genomic estrogen signaling, endoplasmic reticulum, calcium mobilization, phosphatidylinositol 3,4,5-trisphosphate, G protein-coupled receptors, steroid hormone signaling
- MeSH terms
- Animals, Calcium, Cell Line, Cell Membrane, Cell Nucleus, Endoplasmic Reticulum, Estradiol, Estrogens, Humans, Nuclear Envelope, Receptors, Estrogen, Recombinant Fusion Proteins, Transfection, Signal Transduction, Antisense Elements (Genetics), Phosphatidylinositol Phosphates, Phosphatidylinositol 3-Kinases, Protein Transport, Receptors, G-Protein-Coupled, Cell Line, Tumor, Estrogen Receptor alpha, ErbB Receptors
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