GPER1 (G protein-coupled estrogen receptor 1)

2009-03-01 Eric R Prossnitz Affiliation

Cancer Research, Treatment Center, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA

Identity

HGNC

GPER1

LOCATION

7p22.3

IMAGE

LEGEND

Diagram from Entrez Gene.

LOCUSID

2852

ALIAS

GPER,GPR30,CEPR,CMKRL2,DRY12,FEG-1,GPCR-Br,LERGU,LERGU2,LyGPR,mER

DNA/RNA

Note

GPR30 is an estrogen-responsive GPCR (7-transmembrane G protein-coupled receptor).

Alternate transcriptional splice variants (involving the 5 UTR region of the gene) have been characterized. Diagram from Entrez Gene.

Description

The open reading frame of GPR30 is encoded by a single exon (1125 bp) located at chromosome 7p22.3.

Transcription

GPR30 mRNA is about 3.0 kb in human with an 1125 bp open reading frame.

Proteins

Description

The gene encodes a 7-transmembrane G protein-coupled receptor (GPCR) of 375 amino acids.

Expression

GPR30 is widely express throughout the body.

Localisation

Predominantly in the Endoplasmic Reticulum.

Function

Rapid and transcriptional responses to estrogen.
GPR30 is a 7-transmembrane G protein-coupled receptor (GPCR) that has been shown to be an estrogen responsive receptor, expressed predominantly in the endoplasmic reticulum. Signaling occurs via heterotrimeric G protein activation resulting in matrix-metalloproteinase activation, release of heparin-binding EGF and transactivation of EGFR with subsequent MAPK and Akt activation. Calcium mobilization has also been reported in multiple cell types including neurons. This protein plays a role in the rapid non-genomic signaling events often seen following stimulation with estrogen. Transcriptional activation has also been reported secondary to kinase activation. Actions of GPR30 can occur in parallel to those mediated by ERalpha and ERbeta in cells where multiple receptor are expressed, or in the absence of ERalpha and ERbeta. Note that GPR30 does not appear to mediate transcription via classical estrogen-response elements.

Cellular activation by GPR30 and classical estrogen receptors (ERs). Receptor agonists and antagonists (indicated by upward and downward arrows, respectively) are shown for the indicated receptor (Tam, tamoxifen; G-1, GPR30-selective agonist; G15, GPR30-selective antagonist). Nuclear estrogen receptors classically mediate gene regulation although they can also mediate rapid signaling through kinases (not shown). GPR30 is found predominantly in the endoplasmic reticulum and mediates cell activation at least in part through the transactivation of EGFR leading to the stimulation of MAPK, PI3K and other rapid cellular processes, which can result in transcriptional activation.

Homology

High homology between species. Low homology to other GPCRs.

Mutations

Note

None

Implicated in

Entity name

Cancer

Prognosis

Expression levels correlated with HER-2/neu, tumor size and the presence of metastatic disease in breast cancer. Expression correlated with survival and high-risk disease in endometrial cancer. GPR30 mediates estrogen-dependent responses in breast, endometrial and ovarian cancer cell lines including proliferation and migration.

Entity name

Other

Note

GPR30 has been implicated to play a role in estrogen-induced thymic atrophy, estrogen-mediated amelioration of autoimmune encephalomyelitis, depression, pain, vascular function and oocyte maturation.

Bibliography

Pubmed ID	Last Year	Title	Authors
16520733	2006	Virtual and biomolecular screening converge on a selective agonist for GPR30.	Bologa CG et al
9367686	1997	Identification of a gene (GPR30) with homology to the G-protein-coupled receptor superfamily associated with estrogen receptor expression in breast cancer.	Carmeci C et al
17085646	2006	Distribution of GPR30, a seven membrane-spanning estrogen receptor, in primary breast cancer and its association with clinicopathologic determinants of tumor progression.	Filardo EJ et al
19179659	2009	Regulatory role of G protein-coupled estrogen receptor for vascular function and obesity.	Haas E et al
9479505	1998	Discovery of three novel G-protein-coupled receptor genes.	O'Dowd BF et al
8920907	1996	Cloning of human cDNA encoding a novel heptahelix receptor expressed in Burkitt's lymphoma and widely distributed in brain and peripheral tissues.	Owman C et al
18271749	2008	Estrogen signaling through the transmembrane G protein-coupled receptor GPR30.	Prossnitz ER et al
15705806	2005	A transmembrane intracellular estrogen receptor mediates rapid cell signaling.	Revankar CM et al
17403429	2007	GPR30: a novel indicator of poor survival for endometrial carcinoma.	Smith HO et al
9398636	1997	Cloning of cDNAs encoding G protein-coupled receptor expressed in human endothelial cells exposed to fluid shear stress.	Takada Y et al
15539556	2005	Identity of an estrogen membrane receptor coupled to a G protein in human breast cancer cells.	Thomas P et al
18063692	2008	GPR30 contributes to estrogen-induced thymic atrophy.	Wang C et al

Other Information

Locus ID:

NCBI: 2852
MIM: 601805
HGNC: 4485
Ensembl: ENSG00000164850

Variants:

dbSNP: 2852
ClinVar: 2852
TCGA: ENSG00000164850
COSMIC: GPER1

RNA/Proteins

Gene ID	Transcript ID	Uniprot
ENSG00000164850	ENST00000297469	Q99527
ENSG00000164850	ENST00000297469	A0A024R849
ENSG00000164850	ENST00000397088	Q99527
ENSG00000164850	ENST00000397088	A0A024R849
ENSG00000164850	ENST00000397092	Q99527
ENSG00000164850	ENST00000397092	A0A024R849
ENSG00000164850	ENST00000401670	Q99527
ENSG00000164850	ENST00000401670	A0A024R849
ENSG00000164850	ENST00000413368	C9J3W2
ENSG00000164850	ENST00000617001	A0A087WVN0
ENSG00000164850	ENST00000619052	A0A087X0Z4

Expression (GTEx)

Adipose - Subcutaneous

Adipose - Visceral

Adrenal Gland

Artery - Aorta

Artery - Tibial

Bladder

Brain - Amygdala

Brain - Anterior cingulate cortex

Brain - Caudate

Brain - Cerebellar Hemisphere

Brain - Cerebellum

Brain - Cortex

Brain - Frontal Cortex

Brain - Hippocampus

Brain - Hypothalamus

Brain - Nucleus accumbens

Brain - Putamen

Brain - Spinal cord

Brain - Substantia nigra

Breast - Mammary Tissue

Cells - Cultured fibroblasts

Cells - EBV - transformed lymphocytes

Cervix - Ectocervix

Cervix - Endocervix

Colon - Sigmoid

Colon - Transverse

Esophagus - Gastroesophageal Junction

Esophagus - Mucosa

Esophagus - Muscularis

Fallopian Tube

Heart - Atrial Appendage

Heart - Left Ventricle

Kidney - Cortex

Kidney - Medulla

Liver

Lung

Minor Salivary Gland

Muscle - Skeletal

Nerve - Tibial

Ovary

Pancreas

Pituitary

Prostate

Skin - Not Sun Exposed

Skin - Sun Exposed

Small Intestine - Terminal Ileum

Spleen

Stomach

Testis

Thyroid

Uterus

Vagina

Whole Blood

Pathways

Pathway	Source	External ID
Estrogen signaling pathway	KEGG	hsa04915
Estrogen signaling pathway	KEGG	ko04915
Signal Transduction	REACTOME	R-HSA-162582
Signaling by GPCR	REACTOME	R-HSA-372790
GPCR ligand binding	REACTOME	R-HSA-500792
Class A/1 (Rhodopsin-like receptors)	REACTOME	R-HSA-373076
Peptide ligand-binding receptors	REACTOME	R-HSA-375276
GPCR downstream signaling	REACTOME	R-HSA-388396
G alpha (i) signalling events	REACTOME	R-HSA-418594
Endocrine resistance	KEGG	ko01522
Endocrine resistance	KEGG	hsa01522

Protein levels (Protein atlas)

Not detected

Low

Medium

High

References

Pubmed ID	Year	Title	Citations
15705806	2005	A transmembrane intracellular estrogen receptor mediates rapid cell signaling.	678
15539556	2005	Identity of an estrogen membrane receptor coupled to a G protein in human breast cancer cells.	418
15090535	2004	The G protein-coupled receptor GPR30 mediates c-fos up-regulation by 17beta-estradiol and phytoestrogens in breast cancer cells.	147
19179659	2009	Regulatory role of G protein-coupled estrogen receptor for vascular function and obesity.	129
19767412	2010	The unfolding stories of GPR30, a new membrane-bound estrogen receptor.	120
11897506	2002	Epidermal growth factor receptor (EGFR) transactivation by estrogen via the G-protein-coupled receptor, GPR30: a novel signaling pathway with potential significance for breast cancer.	113
19153601	2009	Estrogenic GPR30 signalling induces proliferation and migration of breast cancer cells through CTGF.	111
22495674	2012	Minireview: G protein-coupled estrogen receptor-1, GPER-1: its mechanism of action and role in female reproductive cancer, renal and vascular physiology.	111
20197310	2010	Involvement of estrogen receptor variant ER-alpha36, not GPR30, in nongenomic estrogen signaling.	96
18566127	2008	G protein-coupled receptor 30 localizes to the endoplasmic reticulum and is not activated by estradiol.	95

Citation

Eric R Prossnitz

GPER1 (G protein-coupled estrogen receptor 1)

Atlas Genet Cytogenet Oncol Haematol. 2009-03-01

Online version: http://atlasgeneticsoncology.org/gene/44344/gper1