# GPER1

## Overview
The GPER1 gene encodes the G protein-coupled estrogen receptor 1, a member of the G protein-coupled receptor (GPCR) family, which is integral to non-genomic estrogen signaling. This receptor is characterized by its seven transmembrane alpha-helices, which facilitate its role as a transmembrane receptor involved in various physiological processes (MéndezLuna2016Understanding). GPER1 is expressed in multiple tissues, including the cardiovascular system, where it contributes to vasodilation and cardioprotection (Prossnitz2023The). The receptor's activation influences intracellular signaling pathways, such as cAMP production and calcium mobilization, and can affect gene expression through transcription factors like CREB (Prossnitz2014Estrogen). Clinically, GPER1 is implicated in cardiovascular health and cancer, with certain gene variants linked to increased disease risk (Feldman2017GPER; Ulhaq2021Association). Its interactions with various proteins underscore its complex role in cellular signaling and potential as a therapeutic target.

## Structure
The G protein-coupled estrogen receptor 1 (GPER1) is a member of the GPCR family, characterized by a core structure of seven transmembrane alpha-helices (MéndezLuna2016Understanding). The primary structure of GPER1 includes specific amino acid sequences that facilitate its function as a receptor. The secondary structure is composed of these transmembrane helices, which are connected by intracellular and extracellular loops (MéndezLuna2016Understanding).

GPER1's tertiary structure involves the 3D folding of these helices within the lipid membrane, forming a ligand-binding site primarily in the extracellular regions and transmembrane domains (MéndezLuna2016Understanding). The receptor also contains a PDZ motif in its cytosolic C-terminal domain, which facilitates interactions with various proteins, suggesting its role in forming complexes at the plasma membrane (Ahmadian2023Proteomic).

Post-translational modifications, such as N-glycosylation in the N-terminal domain, are significant for GPER1, affecting its function and interactions (Ahmadian2023Proteomic). These modifications are crucial for glycoprotein maturation and trafficking, as indicated by the enrichment of proteins involved in these processes (Ahmadian2023Proteomic). GPER1 may also have splice variant isoforms, contributing to its functional diversity.

## Function
The G protein-coupled estrogen receptor 1 (GPER1) is a membrane-bound receptor that plays a significant role in mediating non-genomic signaling of estrogens in healthy human cells. GPER1 is involved in various molecular processes, including the regulation of vascular tone and protection against cardiovascular diseases. It facilitates endothelium-dependent vasodilation through the L-arginine-NOS3-NO-cGMP pathway and inhibits contractile factors like endothelin-1, contributing to blood pressure regulation and vasoprotection (Prossnitz2023The; Prossnitz2014Estrogen).

GPER1 activation leads to the production of cAMP, activation of protein kinase A (PKA), and mobilization of calcium from intracellular stores, which are crucial for its signaling functions (Prossnitz2023The; Prossnitz2014Estrogen). It also influences gene expression by activating transcription factors such as CREB and YAP-TAZ, and it can transactivate the epidermal growth factor receptor (EGFR) through matrix metalloproteinases (MMPs) (Prossnitz2023The; Prossnitz2014Estrogen).

GPER1 is expressed in various tissues, including the cardiovascular system, where it exerts cardioprotective effects by reducing oxidative stress and inhibiting vasoconstriction (Luo2020Does). Its role in cellular signaling and gene regulation underscores its importance in maintaining cardiovascular health and potentially other physiological functions.

## Clinical Significance
Mutations and alterations in the GPER1 gene have significant clinical implications across various diseases. In cardiovascular health, a missense variant of GPER1, known as P16L, results in a hypofunctional receptor. This variant is associated with higher blood pressure in women, particularly those who are premenopausal or have resistant hypertension. The P16L variant also correlates with elevated LDL cholesterol levels in women, indicating its role in cholesterol metabolism and cardiovascular disease risk (Feldman2017GPER).

In cancer, GPER1 expression is linked to the progression of several hormone-dependent malignancies, including breast, ovarian, and endometrial cancers. Overexpression of GPER1 is associated with larger tumor size, metastasis, and poor survival outcomes, particularly in breast cancer patients treated with tamoxifen, suggesting a role in tamoxifen resistance (Filardo2018A; Prossnitz2015What). In testicular cancer, GPER1 is overexpressed in seminomas, contributing to cell proliferation and potentially mediated by xeno-estrogens (Chevalier2014Genetic).

GPER1 polymorphisms, such as rs3808350 and rs3808351, are significantly associated with cancer predisposition, especially in the Asian population, highlighting their potential as biomarkers for cancer screening and prognosis (Ulhaq2021Association).

## Interactions
GPER1, also known as GPR30, is involved in various protein interactions that influence its function and localization. It interacts with the postsynaptic density protein PSD-95, membrane-associated guanylate kinases (MAGUKs), protein-kinase A-anchoring protein 5 (AKAP5), and plasma membrane Ca2+-ATPase 4b (PMCA4b). These interactions are crucial for its retention at the plasma membrane and recruitment to dendritic spines, affecting receptor dimerization, signaling, and endocytosis (Gaudet2015The).

GPER1 also forms complexes with proteins such as CLPTM1, PRKCSH, GANAB, and STIM1. CLPTM1, a multi-transmembrane protein, affects the localization of GPER1, potentially leading to its nuclear relocalization. PRKCSH and GANAB are involved in glycosylation and trafficking processes, forming a complex with CLPTM1 that may associate with GPER1 (Ahmadian2023Proteomic).

The interaction with STIM1, a Ca2+ sensor, suggests a role in calcium signaling. GPER1 and STIM1 colocalize in the endoplasmic reticulum, and their interaction is influenced by calcium ionophore treatment, indicating a functional relationship (Ahmadian2023Proteomic).

These interactions highlight GPER1's involvement in complex signaling pathways and its potential role in cellular processes such as calcium signaling and protein trafficking.


## References


[1. (Feldman2017GPER) Ross D. Feldman and Lee E. Limbird. Gper (gpr30): a nongenomic receptor (gpcr) for steroid hormones with implications for cardiovascular disease and cancer. Annual Review of Pharmacology and Toxicology, 57(1):567–584, January 2017. URL: http://dx.doi.org/10.1146/annurev-pharmtox-010716-104651, doi:10.1146/annurev-pharmtox-010716-104651. This article has 109 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1146/annurev-pharmtox-010716-104651)

[2. (Ulhaq2021Association) Zulvikar Syambani Ulhaq, Gita Vita Soraya, Alvi Milliana, and William Ka Fai Tse. Association between gper gene polymorphisms and gper expression levels with cancer predisposition and progression. Heliyon, 7(3):e06428, March 2021. URL: http://dx.doi.org/10.1016/j.heliyon.2021.e06428, doi:10.1016/j.heliyon.2021.e06428. This article has 8 citations and is from a peer-reviewed journal.](https://doi.org/10.1016/j.heliyon.2021.e06428)

[3. (Prossnitz2014Estrogen) Eric R. Prossnitz and Matthias Barton. Estrogen biology: new insights into gper function and clinical opportunities. Molecular and Cellular Endocrinology, 389(1–2):71–83, May 2014. URL: http://dx.doi.org/10.1016/j.mce.2014.02.002, doi:10.1016/j.mce.2014.02.002. This article has 298 citations and is from a peer-reviewed journal.](https://doi.org/10.1016/j.mce.2014.02.002)

[4. (Prossnitz2023The) Eric R. Prossnitz and Matthias Barton. The g protein-coupled oestrogen receptor gper in health and disease: an update. Nature Reviews Endocrinology, 19(7):407–424, May 2023. URL: http://dx.doi.org/10.1038/s41574-023-00822-7, doi:10.1038/s41574-023-00822-7. This article has 48 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1038/s41574-023-00822-7)

[5. (Gaudet2015The) H.M. Gaudet, S.B. Cheng, E.M. Christensen, and E.J. Filardo. The g-protein coupled estrogen receptor, gper: the inside and inside-out story. Molecular and Cellular Endocrinology, 418:207–219, December 2015. URL: http://dx.doi.org/10.1016/j.mce.2015.07.016, doi:10.1016/j.mce.2015.07.016. This article has 91 citations and is from a peer-reviewed journal.](https://doi.org/10.1016/j.mce.2015.07.016)

[6. (Ahmadian2023Proteomic) Maryam Ahmadian Elmi, Nasrin Motamed, and Didier Picard. Proteomic analyses of the g protein-coupled estrogen receptor gper1 reveal constitutive links to endoplasmic reticulum, glycosylation, trafficking, and calcium signaling. Cells, 12(21):2571, November 2023. URL: http://dx.doi.org/10.3390/cells12212571, doi:10.3390/cells12212571. This article has 1 citations and is from a peer-reviewed journal.](https://doi.org/10.3390/cells12212571)

[7. (Prossnitz2015What) Eric R. Prossnitz and Helen J. Hathaway. What have we learned about gper function in physiology and disease from knockout mice? The Journal of Steroid Biochemistry and Molecular Biology, 153:114–126, September 2015. URL: http://dx.doi.org/10.1016/j.jsbmb.2015.06.014, doi:10.1016/j.jsbmb.2015.06.014. This article has 112 citations.](https://doi.org/10.1016/j.jsbmb.2015.06.014)

[8. (Filardo2018A) Edward J. Filardo. A role for g-protein coupled estrogen receptor (gper) in estrogen-induced carcinogenesis: dysregulated glandular homeostasis, survival and metastasis. The Journal of Steroid Biochemistry and Molecular Biology, 176:38–48, February 2018. URL: http://dx.doi.org/10.1016/j.jsbmb.2017.05.005, doi:10.1016/j.jsbmb.2017.05.005. This article has 42 citations.](https://doi.org/10.1016/j.jsbmb.2017.05.005)

[9. (Luo2020Does) Jing Luo and Dongmin Liu. Does gper really function as a g protein-coupled estrogen receptor in vivo? Frontiers in Endocrinology, March 2020. URL: http://dx.doi.org/10.3389/fendo.2020.00148, doi:10.3389/fendo.2020.00148. This article has 98 citations and is from a peer-reviewed journal.](https://doi.org/10.3389/fendo.2020.00148)

[10. (Chevalier2014Genetic) Nicolas Chevalier, Rachel Paul-Bellon, Philippe Camparo, Jean-François Michiels, Daniel Chevallier, and Patrick Fénichel. Genetic variants of gper/gpr30, a novel estrogen-related g protein receptor, are associated with human seminoma. International Journal of Molecular Sciences, 15(1):1574–1589, January 2014. URL: http://dx.doi.org/10.3390/ijms15011574, doi:10.3390/ijms15011574. This article has 29 citations and is from a peer-reviewed journal.](https://doi.org/10.3390/ijms15011574)

[11. (MéndezLuna2016Understanding) David Méndez-Luna, Martiniano Bello, and José Correa-Basurto. Understanding the molecular basis of agonist/antagonist mechanism of gper1/gpr30 through structural and energetic analyses. The Journal of Steroid Biochemistry and Molecular Biology, 158:104–116, April 2016. URL: http://dx.doi.org/10.1016/j.jsbmb.2016.01.001, doi:10.1016/j.jsbmb.2016.01.001. This article has 25 citations.](https://doi.org/10.1016/j.jsbmb.2016.01.001)