Akt causes phosphorylation of endothelial NOS3 (6), which releases nitric oxide (NO) and leads to juxtacrine signalling from endothelial to vascular smooth muscle cells (7), and activation of PKG. These induce additional, rapid (non-genomic) effects such as activation of the l-arginine–endothelial nitric oxide synthase (NOS3)–NO–cGMP pathway (in combination with mobilization of calcium stores). HB-EGF then transactivates the EGF receptor (5), which in turn activates MAPK (ERK1/2), Akt and other pathways.
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Activation of SRC via G proteins can also lead to activation of matrix metalloproteinases (MMPs) (5) that cleave pro-heparin-binding epidermal growth factor (HB-EGF) (5), releasing free HB-EGF. GPER activation can also lead to regulation of gene expression via activation of the YAP–TAZ transcription factors via Rho–ROCK signalling (4). G protein activation also leads to calcium (Ca 2+) mobilization from intracellular stores, which activates PKC and leads to activation of plasma membrane calcium channels. GPER activates several heterotrimeric G proteins (2), leading to multiple downstream cascades, including cAMP production (3) and activation of PKA (3) and CREB (3). 17β-Oestradiol (E2), selective agonists such as G-1, or selective oestrogen receptor modulators (SERMs) and selective oestrogen receptor downregulators and/or degraders (SERDs) activate GPER (1), which is localized predominantly intracellularly at the endoplasmic reticulum. Non-genomic and genomic signalling pathways are activated by oestrogen and oestrogenic ligands (in yellow) through binding to the three known oestrogen receptors, oestrogen receptor-α (ERα), oestrogen receptor-β (ERβ) and the G protein-coupled oestrogen receptor (GPER).
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We also discuss the first clinical trial evaluating a GPER-selective drug and the opportunity of repurposing licensed drugs for the targeting of GPER in clinical medicine.
We will review molecular, cellular and pharmacological aspects of GPER signalling and function, its contribution to physiology, health and disease, and the potential of GPER to serve as a therapeutic target and prognostic indicator of numerous diseases. Following up on our previous Review of 2011, we herein summarize the progress made in the field of GPER research over the past decade. Oestrogen mimetics (such as phytooestrogens and xenooestrogens including endocrine disruptors) and licensed drugs such as selective oestrogen receptor modulators (SERMs) and downregulators (SERDs) also modulate oestrogen receptor activity in both health and disease. GPER, which dates back more than 450 million years in evolution, mediates both rapid signalling and transcriptional regulation. Oestrogens and oestrogen mimetics mediate their effects via the cytosolic and nuclear receptors oestrogen receptor-α (ERα) and oestrogen receptor-β (ERβ) and membrane subpopulations as well as the 7-transmembrane G protein-coupled oestrogen receptor (GPER). In premenopausal women, endogenous oestrogens protect against cardiovascular, metabolic and neurological diseases and are involved in hormone-sensitive cancers such as breast cancer. Oestrogens and their receptors contribute broadly to physiology and diseases.
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