Membrane estrogen receptor

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Membrane estrogen receptors (mERs) are a group of receptors which bind estrogen. [1] [2] Unlike nuclear estrogen receptors, which mediate their effects via slower genomic mechanisms, mERs are cell surface receptors that rapidly alter cell signaling via modulation of intracellular signaling cascades. [3] [4]

Contents

Nuclear estrogen receptors such as ERα and ERβ become mERs through palmitoylation, a post-translational modification that enhances ER association with caveolin-1 to enable trafficking of ERs to the membrane or membrane caveolae. [5] [6] Other putative mERs include GPER (GPR30), GPRC6A, ER-X, ERx and Gq-mER. [3] [7] [8] [9]

ERa/ERb becoming mERs through trafficking to the membrane by caveolins, following palmitoylation. MER localization.pdf
ERα/ERβ becoming mERs through trafficking to the membrane by caveolins, following palmitoylation.

Structure-function relationship

In mice and humans, ERβ localization in the plasma membrane occurs after palmitoylation on cysteine 418. [10] Dimerization of mERs appears necessary for their function in rapid cell signaling. [11]

Signaling mechanisms

G-protein coupled receptors

Various electrophysiological studies support E2 signaling via GPCRs. [12] [13] [14] 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. [15] [16]

Gq-coupled mERs (Gq-mERs) activation has been demonstrated to rapidly increase membrane excitability various neuronal cell types by desensitizing GABAB receptor coupling to G protein-coupled inwardly rectifying K+ channels (GIRKs). [17] [18] [19]

mGluRs

Localization of mERs in caveolae allows them to be held in close proximity to specific receptors such as mGluRs. [20] Various studies have demonstrated mER's ability to activate mGluR signaling, even in the absence of glutamate. [21] [22] [23] 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. [24]

Clinical significance

Membrane estrogen receptors have been implicated in reproductive, cardiovascular, neural, and immune function, including cancer, neurodegenerative disease, and cardiovascular disorders. [25] [26]

Cancer

GPER1 pathways modify local inflammation and strengthen cellular immune responses in breast cancer and melanoma, making it a strong prognostic marker. [27] [28] [29]

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. [30] [31]

Cardiovascular disorders

mERβ has been demonstrated to mitigate cardiac cell pathology caused by angiotensin II. [10] [32] 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. [33]

Addiction

Propensity to addiction appears to be mediated by sex hormones such as estrogen. [34] 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. [35] [36]

See also

Related Research Articles

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Estrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal activity: estrone (E1), estradiol (E2), and estriol (E3). Estradiol, an estrane, is the most potent and prevalent. Another estrogen called estetrol (E4) is produced only during pregnancy.

<span class="mw-page-title-main">Estradiol</span> Chemical compound

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<span class="mw-page-title-main">Steroid hormone</span> Substance with biological function

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<span class="mw-page-title-main">Estrogen receptor</span> Proteins activated by the hormone estrogen

Estrogen receptors (ERs) are a group of proteins found inside cells. They are receptors that are activated by the hormone estrogen (17β-estradiol). Two classes of ER exist: nuclear estrogen receptors, which are members of the nuclear receptor family of intracellular receptors, and membrane estrogen receptors (mERs), which are mostly G protein-coupled receptors. This article refers to the former (ER).

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<span class="mw-page-title-main">Nuclear receptor</span> Protein

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<span class="mw-page-title-main">GPER</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">Estrogen receptor beta</span> Protein-coding gene in the species Homo sapiens

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References

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