Structural analysis of estrogen receptors: interaction between estrogen receptors and cav-1 within the caveolae†

Pastore, Mayra B.; Landeros, Rosalina Villalon; Chen, Dong‐bao; Magness, Ronald R.

doi:10.1093/biolre/ioy188

Cited by 18 publications

(16 citation statements)

References 82 publications

(155 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Estrogen receptors (both ERa and ERb) functionally couple to mGluRs in various brain regions such as the hippocampus, striatum, and hypothalamus (Dewing et al, 2007;Grove-Strawser et al, 2010;Huang and Woolley, 2012;Oberlander and Woolley, 2016). ERa and mGluRs are associated in complexes at the cell membrane with caveolin proteins (Razandi et al, 2002;Boulware et al, 2007;Dewing et al, 2007;Meitzen et al, 2013;Tabatadze et al, 2015;Pastore et al, 2019). Our results support the possibility that a similar coupling of ERa and mGluR1 occurs in the VTA of females and that this interaction is an important regulator of the sensitivity of DA neurons to ethanol excitation.…”

supporting

confidence: 74%

Estrogen Receptor α Regulates Ethanol Excitation of Ventral Tegmental Area Neurons and Binge Drinking in Female Mice

Vandegrift

Hilderbrand

Satta

et al. 2019

Preprint

View full text Add to dashboard Cite

Elevations in estrogen (17b-estradiol, E2) are associated with increased alcohol drinking by women and experimentally in rodents. E2 alters the activity of the dopamine system, including the ventral tegmental area (VTA) and its projection targets, which plays an important role in binge drinking. A previous study demonstrated that during high E2 states, VTA dopamine neurons in female mice are more sensitive to ethanol excitation. However, the mechanisms responsible for the ability of E2 to enhance ethanol sensitivity of VTA dopamine neurons have not been investigated. In this study, we used selective agonists and antagonists to examine the role of estrogen receptor subtypes (ERa and ERb) in regulating the ethanol sensitivity of VTA dopamine neurons and found that ERa promotes the enhanced ethanol response of VTA dopamine neurons. We also demonstrated that the E2-induced increase in ethanol excitation requires the activity of the metabotropic glutamate receptor, mGluR1, which is known to couple with ERa at the plasma membrane. To investigate the behavioral relevance of these findings, we administered lentivirus expressing short hairpin RNAs targeting either ERa or ERb into the VTA and found that knockdown of each receptor in the VTA reduced binge-like ethanol drinking in female, but not male, mice. Reducing ERa in the VTA had a more dramatic effect on binge-like drinking than reducing ERb, consistent with the ability of ERa to alter ethanol sensitivity of dopamine neurons. These results provide important insight into sex-specific mechanisms that drive excessive alcohol drinking. Significance StatementEstrogen has potent effects on the dopamine system and increases the vulnerability of females to develop addiction to substances such as cocaine and alcohol. We investigated the mechanisms by which estrogen increases the response of dopamine neurons in the ventral tegmental area to ethanol. We found that activation of the estrogen receptor, ERa, increased the ethanol-induced excitation of dopamine neurons and that this required the metabotropic glutamate receptor mGluR1. We also demonstrated that estrogen receptors in the ventral tegmental area regulate binge-like alcohol drinking by female, but not male, mice. The influence of estrogen receptors on binge drinking in female mice suggests that treatments for alcohol use disorder in women may need to account for this sex difference.

show abstract

supporting

confidence: 74%

Estrogen Receptor α Regulates Ethanol Excitation of Ventral Tegmental Area Neurons and Binge Drinking in Female Mice

Vandegrift

Hilderbrand

Satta

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…Caveolins, scaffolding proteins, are necessary for steroid nuclear receptor trafficking to the cell membrane . Additionally, CAV proteins appear to regulate the type of mGluR that associates with ERs .…”

Section: Discussionmentioning

confidence: 99%

ERαΔ4, an ERα splice variant missing exon4, interacts with caveolin‐3 and mGluR2/3

Wong

Scott

Johnson

et al. 2019

J Neuroendocrinology

View full text Add to dashboard Cite

The two isoforms of the nuclear estrogen receptor, ERα and ERβ are widely expressed in the central nervous system. Although they were first described as nuclear receptors, both isoforms have also been found at the cell membrane where they mediate cell signaling. Surface biotinylation studies using neuronal and glial primary cultures label an alternatively spliced form of ERα. The 52 kDa protein, ERαΔ4, is missing exon 4 and is highly expressed in membrane fractions derived from cultured cells. In vivo, both full‐length (66 kDa) ERα and ERαΔ4 are present in membrane fractions. In response to estradiol, full‐length ERα and ERαΔ4 are initially trafficked to the membrane, and then internalized in parallel. Previous studies determined that only the full‐length ERα associates with metabotropic glutamate receptor‐1a (mGluR1a), initiating cellular signaling. The role of ERαΔ4, remained to be elucidated. Here, we report ERαΔ4 trafficking, association with mGluR2/3, and downstream signaling in female rat arcuate nucleus (ARH). Caveolin (CAV) proteins are needed for ER transport to the cell membrane, and using co‐immunoprecipitation CAV‐3 was shown to associate with ERαΔ4. CAV‐3 was necessary for ERαΔ4 trafficking to the membrane: in the ARH, microinjection of CAV‐3 siRNA reduced CAV‐3 and ERαΔ4a in membrane fractions by 50%, and 60%, respectively. Moreover, co‐immunoprecipitation revealed that ERαΔ4 associated with inhibitory mGluRs, mGluR2/3. Estrogen benzoate (EB) treatment (5 μg; s.c.; every 4 days; three cycles) reduced levels of cAMP, an effect attenuated by antagonizing mGluR2/3. Following EB treatment, membrane levels of ERαΔ4 and mGluR2/3 were reduced implying ligand‐induced internalization. These results implicate ERαΔ4 in an estradiol‐induced inhibitory cell signaling in the ARH.

show abstract

“…In colon cancer cells, Galluzzo and her colleagues found that E 2 β could stimulate the association between ERβ and caveolae signature protein caveolin-1 [123]. Nonetheless, a recent study did not find direct ERβ targeting to the plasma membrane caveolae in UAEC [93]. Thus, it is highly likely that the role of ERβ in rapid uterine vasodilation to estrogen, if any, is an indirect mechanism that is yet to be determined.…”

Section: Membrane Ers and Estrogen-induced Uterine Vasodilation In Prmentioning

confidence: 99%

“…Nonetheless, there is solid evidence that both ERα and ERβ are present on the plasma membrane. In vascular EC, ERα has been shown to be partitioned into the specialized plasma microdomains, called caveolae, by interacting with caveolin-1 directly [71,92,93]. Both the plasma membrane-bound ERα and ERβ are responsible for the estrogen-stimulated rapid release of NO in UAEC in distinct ways [94]; however, the importance of this pathway in uterine vasodilation is unclear.…”

Section: Membrane Ers and Estrogen-induced Uterine Vasodilation In Prmentioning

confidence: 99%

“…Although ERα has been shown to be localized on the plasma membrane of UAEC in in vitro culture [39,93], the importance of membrane-targeted ERα in estrogen-induced uterine dilation is yet to be fully determined. ERβ is also localized on the plasma membrane in other types of EC such as bovine aortic EC [122] and non-EC cancer cells [123].…”

Section: Membrane Ers and Estrogen-induced Uterine Vasodilation In Prmentioning

confidence: 99%

See 1 more Smart Citation

Estrogen Receptors and Estrogen-Induced Uterine Vasodilation in Pregnancy

Bai

et al. 2020

IJMS

Self Cite

View full text Add to dashboard Cite

Normal pregnancy is associated with dramatic increases in uterine blood flow to facilitate the bidirectional maternal–fetal exchanges of respiratory gases and to provide sole nutrient support for fetal growth and survival. The mechanism(s) underlying pregnancy-associated uterine vasodilation remain incompletely understood, but this is associated with elevated estrogens, which stimulate specific estrogen receptor (ER)-dependent vasodilator production in the uterine artery (UA). The classical ERs (ERα and ERβ) and the plasma-bound G protein-coupled ER (GPR30/GPER) are expressed in UA endothelial cells and smooth muscle cells, mediating the vasodilatory effects of estrogens through genomic and/or nongenomic pathways that are likely epigenetically modified. The activation of these three ERs by estrogens enhances the endothelial production of nitric oxide (NO), which has been shown to play a key role in uterine vasodilation during pregnancy. However, the local blockade of NO biosynthesis only partially attenuates estrogen-induced and pregnancy-associated uterine vasodilation, suggesting that mechanisms other than NO exist to mediate uterine vasodilation. In this review, we summarize the literature on the role of NO in ER-mediated mechanisms controlling estrogen-induced and pregnancy-associated uterine vasodilation and our recent work on a “new” UA vasodilator hydrogen sulfide (H2S) that has dramatically changed our view of how estrogens regulate uterine vasodilation in pregnancy.

show abstract

Structural analysis of estrogen receptors: interaction between estrogen receptors and cav-1 within the caveolae†

Cited by 18 publications

References 82 publications

Estrogen Receptor α Regulates Ethanol Excitation of Ventral Tegmental Area Neurons and Binge Drinking in Female Mice

Estrogen Receptor α Regulates Ethanol Excitation of Ventral Tegmental Area Neurons and Binge Drinking in Female Mice

ERαΔ4, an ERα splice variant missing exon4, interacts with caveolin‐3 and mGluR2/3

Estrogen Receptors and Estrogen-Induced Uterine Vasodilation in Pregnancy

Contact Info

Product

Resources

About