Estrogen receptor alpha and G-protein coupled receptor 30 mediate the neuroprotective effects of 17β-estradiol in novel murine hippocampal cell models

Gingerich, Sarah; Kim, G.L.; Chalmers, J. P.; Koletar, Margaret M.; Wang, X.; Wang, Y.; Belsham, Denise D.

doi:10.1016/j.neuroscience.2010.06.076

Cited by 157 publications

(119 citation statements)

References 42 publications

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“…Immortalized mouse mHippoE-14 hippocampal cell lines (Gingerich et al, 2010) were obtained commercially (Cedarlane, USA). Cells were transduced with a lentiviral vector containing the bioluminescent circadian reporter gene Per2::Luc and a blasticidin resistance gene (Liu et al, 2007).…”

Section: Hippocampal Cell Culturementioning

confidence: 99%

The mood stabilizer valproic acid opposes the effects of dopamine on circadian rhythms

et al. 2016

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a b s t r a c tEndogenous circadian (~24 h) clocks regulate key physiological and cognitive processes via rhythmic expression of clock genes. The main circadian pacemaker is the hypothalamic suprachiasmatic nucleus (SCN). Mood disorders, including bipolar disorder (BD), are commonly associated with disturbed circadian rhythms. Dopamine (DA) contributes to mania in BD and has direct impact on clock gene expression. Therefore, we hypothesized that high levels of DA during episodes of mania contribute to disturbed circadian rhythms in BD. The mood stabilizer valproic acid (VPA) also affects circadian rhythms. Thus, we further hypothesized that VPA normalizes circadian disturbances caused by elevated levels of DA. To test these hypotheses, we examined locomotor rhythms and circadian gene cycling in mice with reduced expression of the dopamine transporter (DAT-KD mice), which results in elevated DA levels and manialike behavior. We found that elevated DA signaling lengthened the circadian period of behavioral rhythms in DAT-KD mice and clock gene expression rhythms in SCN explants. In contrast, we found that VPA shortened circadian period of behavioral rhythms in DAT-KD mice and clock gene expression rhythms in SCN explants, hippocampal cell lines, and human fibroblasts from BD patients. Thus, DA and VPA have opposing effects on circadian period. To test whether the impact of VPA on circadian rhythms contributes to its behavioral effects, we fed VPA to DAT-deficient Drosophila with and without functioning circadian clocks. Consistent with our hypothesis, we found that VPA had potent activity-suppressing effects in hyperactive DAT-deficient flies with intact circadian clocks. However, these effects were attenuated in DAT-deficient flies in which circadian clocks were disrupted, suggesting that VPA functions partly through the circadian clock to suppress activity. Here, we provide in vivo and in vitro evidence across species that elevated DA signaling lengthens the circadian period, an effect remediated by VPA treatment. Hence, VPA may exert beneficial effects on mood by normalizing lengthened circadian rhythm period in subjects with elevated DA resulting from reduced DAT.

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Section: Hippocampal Cell Culturementioning

confidence: 99%

The mood stabilizer valproic acid opposes the effects of dopamine on circadian rhythms

et al. 2016

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“…Through genomic and nongenomic mechanisms, E2 modulates neuronal excitability and rapidly increases signal transmission by regulating both NMDA and non-NMDA glutamate receptors (NMDARs) (Wong and Moss, 1992;Foy et al, 1999). The GPR30 receptor may act together with intracellular estrogen receptors to activate cell-signaling pathways to promote neuron survival after global ischemia (Hazell et al, 2009;Gingerich et al, 2010;Lebesgue et al, 2010). However, the role of GPR30 in neuroprotection against excitotoxic neuronal death induced by NMDA exposure remains unknown.…”

Section: Introductionmentioning

confidence: 99%

G-Protein-Coupled Receptor 30 Mediates Rapid Neuroprotective Effects of Estrogen via Depression of NR2B-Containing NMDA Receptors

Liu

Zhang²,

Guo³

et al. 2012

J. Neurosci.

148

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17-␤-Estradiol (E2)is a steroid hormone involved in neuroprotection against excitotoxicity and other forms of brain injury. Through genomic and nongenomic mechanisms, E2 modulates neuronal excitability and signal transmission by regulating NMDA and non-NMDA receptors. However, the mechanisms and identity of the receptors involved remain unclear, even though studies have suggested that estrogen G-protein-coupled receptor 30 (GPR30) is linked to protection against ischemic injury. In the culture cortical neurons, treatment with E2 and the GPR30 agonist G1 for 45 min attenuated the excitotoxicity induced by NMDA exposure. The acute neuroprotection mediated by GPR30 is dependent on G-protein-coupled signals and ERK1/2 activation, but independent on transcription or translation. Knockdown of GPR30 using short hairpin RNAs (shRNAs) significantly reduced the E2-induced rapid neuroprotection. Patch-clamp recordings revealed that GPR30 activation depressed exogenous NMDA-elicited currents. Short-term GPR30 activation did not affect the expression of either NR2A-or NR2B-containing NMDARs; however, it depressed NR2B subunit phosphorylation at Ser-1303 by inhibiting the dephosphorylation of death-associated protein kinase 1 (DAPK1). DAPK1 knockdown using shRNAs significantly blocked NR2B subunit phosphorylation at Ser-1303 and abolished the GPR30-mediated depression of exogenous NMDA-elicited currents. Lateral ventricle injection of the GPR30 agonist G1 (0.2 g) provided significant neuroprotection in the ovariectomized female mice subjected to middle cerebral artery occlusion. These findings provide direct evidence that fast neuroprotection by estradiol is partially mediated by GPR30 and the subsequent downregulation of NR2B-containing NMDARs. The modulation of DAPK1 activity by GPR30 may be an important mediator of estradiol-dependent neuroprotection.

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“…Thus, acute application of the GPER1 agonist G1 reduced ischemiadamage to hippocampal neurons in aged female rats (Lebesgue et al, 2010). In addition, GPER1 activation mirrors the effects of E2 by increasing the survival of cortical and hippocampal neurons exposed to neurotoxic insults (Gingerich et al, 2010;Liu et al, 2011;Liu et al, 2012). The cellular mechanisms underlying the neuroprotective actions of GPER1 involve activation of ERK1/2 signalling (Liu et al, 2012;Liu et al, 2011) and are associated with selective downregulation of GluN2B-containing NMDA receptors (Liu et al, 2012).…”

Section: Estrogen and Neuroprotectionmentioning

confidence: 97%

“…In neurons GPER1 is reported to couple to PI 3-kinase and/or ERK signalling cascades to regulate cell viability (Gingerich et al, 2010;Abdelhamid et al, 2011;Liu et al, 2012).…”

Section: Gper1 Signallingmentioning

confidence: 99%

Emerging roles for the novel estrogen-sensing receptor GPER1 in the CNS

2017

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Keywords: G protein coupled estrogen receptor, hippocampal synaptic function; receptor trafficking; learning and memory; neuroprotection; synaptic plasticity. Estrogens play a key role in regulating reproductive and neuroendocrine function by activating classical nuclear steroid receptors that act as ligand gated transcription factors.However evidence is growing that estrogens also promote rapid non-genomic responses via activation of membrane-associated estrogen receptors. The G protein-coupled estrogen receptor (GPER1; also known as GPR30) has been identified as one of the main estrogensensitive receptors responsible for the rapid non-genomic actions of estrogen. In recent years, our understanding of the CNS actions of GPER1s has significantly increased following the development of selective pharmacological tools and via the use of transgenic technologies to knockout GPER1 in mice. Here we review recent advances that have been made to uncover the role of GPER1s in the CNS.Introduction.

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Estrogen receptor alpha and G-protein coupled receptor 30 mediate the neuroprotective effects of 17β-estradiol in novel murine hippocampal cell models

Cited by 157 publications

References 42 publications

The mood stabilizer valproic acid opposes the effects of dopamine on circadian rhythms

The mood stabilizer valproic acid opposes the effects of dopamine on circadian rhythms

G-Protein-Coupled Receptor 30 Mediates Rapid Neuroprotective Effects of Estrogen via Depression of NR2B-Containing NMDA Receptors

Emerging roles for the novel estrogen-sensing receptor GPER1 in the CNS

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