Membrane estrogen receptors (mERs) are a group of

receptor Receptor may refer to: * Sensory receptor, in physiology, any neurite structure that, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochemistry), in biochemistry, a protein molecule that receives and respond ...

s which bind

estrogen Estrogen (also spelled oestrogen in British English; see spelling differences) is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three ...

. Unlike nuclear

estrogen receptor Estrogen receptors (ERs) are proteins found in cell (biology), cells that function as receptor (biochemistry), receptors for the hormone estrogen (17β-estradiol). There are two main classes of ERs. The first includes the intracellular estrogen ...

s, which mediate their effects via slower

genomic Genomics is an interdisciplinary field of molecular biology focusing on the structure, function, evolution, mapping, and editing of genomes. A genome is an organism's complete set of DNA, including all of its genes as well as its hierarchical, ...

mechanisms, mERs are

cell surface receptor Cell surface receptors (membrane receptors, transmembrane receptors) are receptors that are embedded in the plasma membrane of cells. They act in cell signaling by receiving (binding to) extracellular molecules. They are specialized integra ...

s that rapidly alter

cell signaling In biology, cell signaling (cell signalling in British English) is the Biological process, process by which a Cell (biology), cell interacts with itself, other cells, and the environment. Cell signaling is a fundamental property of all Cell (biol ...

via modulation of

intracellular This glossary of biology terms is a list of definitions of fundamental terms and concepts used in biology, the study of life and of living organisms. It is intended as introductory material for novices; for more specific and technical definitions ...

signaling cascades. Nuclear estrogen receptors such as ERα and

ERβ Estrogen receptor beta (ERβ) also known as NR3A2 (nuclear receptor subfamily 3, group A, member 2) is one of two main types of estrogen receptor—a nuclear receptor which is activated by the sex hormone estrogen. In humans ERβ is encoded by t ...

become mERs through palmitoylation, a

post-translational modification In molecular biology, post-translational modification (PTM) is the covalent process of changing proteins following protein biosynthesis. PTMs may involve enzymes or occur spontaneously. Proteins are created by ribosomes, which translation (biolog ...

that enhances ER association with caveolin-1 to enable trafficking of ERs to the membrane or membrane

caveolae In biology, caveolae (Latin for "little caves"; singular, caveola), which are a special type of lipid raft, are small (50–100 nanometer) invaginations of the plasma membrane in the cells of many vertebrates. They are the most abundant surface fe ...

. Other putative mERs include

GPER G protein-coupled estrogen receptor 1 (GPER), also known as G protein-coupled receptor 30 (GPR30), is a protein that in humans is encoded by the ''GPER'' gene. GPER binds to and is activated by the female sex hormone estradiol and is responsible ...

(GPR30), GPRC6A, ER-X, ERx and G_q-mER.

Structure-function relationship

In mice and humans, ERβ localization in the plasma membrane occurs after palmitoylation on cysteine 418. Dimerization of mERs appears necessary for their function in rapid cell signaling.

Signaling mechanisms

G-protein coupled receptors

Various electrophysiological studies support E2 signaling via GPCRs. mERs are thought to activate G-protein coupled receptors to regulate L-type Ca2+ channels and activate protein kinase A (PKA), protein kinase C (PKC), and mitogen activated protein kinase (MAPK) signaling cascades. Gq-coupled mERs (Gq-mERs) activation has been demonstrated to rapidly increase membrane excitability various neuronal cell types by desensitizing GABA_B receptor coupling to G protein-coupled inwardly rectifying K+ channels (GIRKs).

mGluRs

Localization of mERs in caveolae allows them to be held in close proximity to specific receptors such as mGluRs. Various studies have demonstrated mER's ability to activate mGluR signaling, even in the absence of glutamate. ER/mGluR signaling is thought to be highly relevant for female motivational behavior. Interestingly, modification of caveolin expression appears to alter the nature of ER-mGluR interactions.

Clinical significance

Membrane estrogen receptors have been implicated in reproductive, cardiovascular, neural, and immune function, including cancer, neurodegenerative disease, and cardiovascular disorders.

Cancer

GPER1 pathways modify local inflammation and strengthen cellular immune responses in breast cancer and melanoma, making it a strong prognostic marker.

Neurodegenerative disease

mERs have a demonstrated neuroprotective effect against neurodegenerative disorders like Parkinson's disease, which is thought to underlie the lower incidence of the disorder in women compared to men.

Cardiovascular disorders

mERβ has been demonstrated to mitigate cardiac cell pathology caused by

angiotensin II Angiotensin is a peptide hormone that causes vasoconstriction and an increase in blood pressure. It is part of the renin–angiotensin system, which regulates blood pressure. Angiotensin also stimulates the release of aldosterone from the ...

. Activation of mER but not nuclear ER signaling in vascular epithelial cells promotes protection against vascular injury in mice. Striatin, a scaffolding protein that links mERs to membrane caveolae, is necessary for this effect.

Addiction

Propensity to addiction appears to be mediated by sex hormones such as estrogen. In neural reward circuity, nuclear ERs are not commonly expressed, and mERs have been demonstrated to act on mGluR5 to facilitate psychostimulant-induced behavioral and neurochemical effects.

References

{{Estrogenics G protein-coupled receptors Human proteins Human female endocrine system