Membrane estrogen receptor

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]

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 G_q-mER.^[3][7][8][9]

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 GABA_B 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

• Membrane steroid receptor
• Estrogen receptor