The G-protein-coupled estrogen receptor GPER in health and disease

Prossnitz, Eric R.; Barton, Matthias

doi:10.1038/nrendo.2011.122

Cited by 773 publications

(723 citation statements)

References 200 publications

(282 reference statements)

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“…In the female hippocampus, a low NO level is due to low E2. The biological effects of estrogen are mediated by binding to two intracellular ERs, ERα and ERβ (17). ERα is critical for reproductive function.…”

Section: Discussionmentioning

confidence: 99%

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Hippocampal nitric oxide contributes to sex difference in affective behaviors

Luo

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Mechanisms underlying the female preponderance in affective disorders are poorly understood. Here we show that hippocampal nitric oxide (NO) plays a role in the sex difference of depressionlike behaviors in rodents. Female mice had substantially lower NO production in the hippocampus and were significantly more likely to display negative affective behaviors than their male littermates. Eliminating the difference in the basal hippocampal NO level between male and female mice mended the sex gap of affective behaviors. Estradiol exerted a positive control on hippocampal NO production via estrogen receptor-β-mediated neuronal NO synthase expression. Thus, low estrogen in the female hippocampus accounts for lower local NO than in the male hippocampus. Although estrogen has important significance in modulating affective behaviors, it is not estrogen but NO in the hippocampus that mediates the sex difference of affective behaviors directly, because hippocampal NO was necessary for the behavioral effects of estradiol, and NO was an independent factor in modulating behaviors. Stress promoted hippocampal NO production in males because of glucocorticoid release, thus leading to local NO excess. In contrast, stress suppressed NO production in females because of decreased estrogen, thereby resulting in hippocampal NO shortage. Whereas activating cAMP response element binding protein (CREB) rescued the depression-like effects of the intrahippocampal NO donor diethylenetriamine/nitric oxide adduct (DETA/NONOate), inactivating CREB abolished the antidepressant-like effects of the intrahippocampal NO donor DETA/NONOate. Our findings suggest a molecular mechanism underlying the sex difference of affective behaviors.A ffective disorders such as depression and anxiety, lifethreatening and highly prevalent stress-related disorders, rank among the top causes of worldwide disease burden and disability (1, 2). It is commonly suggested that a female preponderance in depression and anxiety is universal and substantial. The prevalence of depression and anxiety for women is approximately twice that for men (2-6). Although there are advocates for the implications of hypothalamic-pituitary-adrenal axis hyperactivity in the sex differentiation in some expressions of both depression and anxiety (7), it is not clear what underlies the sex gap in these affective disorders.Neuronal nitric oxide synthase (nNOS) has been implicated in the psychiatric disorders characterized by depression (8, 9), schizophrenia (10), and aggressiveness (11). We recently demonstrated that hippocampal nNOS mediates the stress-related depressive behaviors of glucocorticoids (9) and the role of 5-hydroxytryptamine receptor 1A (5-HT1A) receptor in modulating anxiety-related behaviors (12). Evidence from clinical and biological studies indicates that the hippocampus plays an important role in major depression disorder (13). We found that chronic mild stress (CMS) increased hippocampal NO production by nNOS in male mice (6-9). In contrast, CMS diminished hippocampal NO prod...

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Section: Discussionmentioning

confidence: 99%

“…2E). The actions of estrogen are ascribed to two nuclear estrogen receptors (ERs), ERα and ERβ (17). Beneficial effects of estrogens on mood are mainly due to ERβ signaling (18).…”

Section: Hippocampal No Is Essential For the Sex Difference Of Affectivementioning

confidence: 99%

Hippocampal nitric oxide contributes to sex difference in affective behaviors

Luo

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…40 The non-selective ER antagonist ICI 182780 and selective ER modulators, such as tamoxifen and raloxifene, have been shown to act as GPR30 ligands. 46 Moreover, both GPR30 and ER are required for estrogen action in some situations, whereas GPR30 can act alone in the absence of ER, 46,47 suggesting a complex network between GPR30 and ER.…”

Section: Action Of Estrogen On the Cardiovascular Systemmentioning

confidence: 99%

Hormonal effects on blood vessels

Akishita

2012

Hypertens Res

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The incidence of cardiovascular disease (CVD) is lower in younger women than in men of the same age, but it increases after menopause, implicating the atheroprotective action of endogenous estrogen. Although observational studies have suggested the efficacy of estrogen therapy in postmenopausal women, placebo-controlled, randomized trials, such as the Women's Health Initiative, have not confirmed effects of estrogen therapy on CVD. Conversely, basic, experimental research has progressed and provided mechanistic insight into estrogen's action on blood vessels. By contrast, the vascular effects of androgens remain poorly understood and have been controversial for a long time. In recent years, an increasing body of evidence has suggested that androgens may exert protective effects against the development of atherosclerosis, at least in elderly men. Epidemiological studies have shown that the incidence of and mortality due to CVD were increased in elderly men with low testosterone levels, although the efficacy of androgen therapy remains unknown. Furthermore, recent experimental studies have demonstrated the direct action of androgens on the vasculature. In this review, we illustrate the effects of sex steroids on the cardiovascular system, focusing on the action of testosterone on the blood vessels.

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“…These effects are mainly mediated through classical estrogen receptor (ER) a and ERb, which are both expressed in endothelial cells (Sobrino et al, 2010). A third type of ER, G-protein coupled which is primarily localized to the endoplasmic reticulum, named GPER, mediates several rapid and non-genomic estrogen effects (Prossnitz and Barton, 2011).…”

Section: Introductionmentioning

confidence: 99%

Estradiol, acting through estrogen receptor alpha, restores dimethylarginine dimethylaminohydrolase activity and nitric oxide production in oxLDL-treated human arterial endothelial cells

Novella

Laguna-Fernández

Lázaro-Franco

et al. 2013

Molecular and Cellular Endocrinology

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a b s t r a c tAsymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide (NO) synthase. ADMA accumulation, mainly due to a decreased dimethylarginine dimethylaminohydrolase (DDAH) activity, has been related to the development of cardiovascular diseases. We investigate whether estradiol prevents the changes induced by oxidized low density lipoprotein (oxLDL) on the DDAH/ADMA/NO pathway in human umbilical artery endothelial cells (HUAEC). HUAEC were exposed to estradiol, native LDL (nLDL), oxLDL and their combinations for 24 h. In some experiments, cells were also exposed to the unspecific estrogen receptor (ER) antagonist ICI 182780, the specific ERa antagonist MPP or specific agonists for ERa, ERb and GPER. ADMA concentration was measured by HPLC and concentration of NO by amperometry. Protein expression and DDAH activity were measured by immunoblotting and an enzymatic method, respectively. oxLDL, but not nLDL, increased ADMA concentration with a concomitant decrease on DDAH activity. oxLDL reduced eNOS protein and NO production. Estradiol alone had no effects on DDAH/ADMA/NO pathway, but increased the attenuated endothelial NO production induced by oxLDL by reduction in ADMA and preventing loss of eNOS protein levels. ICI 182780 and MPP completely abolished these effects of estradiol on oxLDL-exposed cells. ERa agonist, but not ERb and GPER agonists, mirrored estradiol effects on NO production. In conclusion, estradiol restores (1) DDAH activity, and therefore ADMA levels, and (2) NO production impaired by oxLDL in HUAEC acting through ERa.

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The G-protein-coupled estrogen receptor GPER in health and disease

Cited by 773 publications

References 200 publications

Hippocampal nitric oxide contributes to sex difference in affective behaviors

Hippocampal nitric oxide contributes to sex difference in affective behaviors

Hormonal effects on blood vessels

Estradiol, acting through estrogen receptor alpha, restores dimethylarginine dimethylaminohydrolase activity and nitric oxide production in oxLDL-treated human arterial endothelial cells

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