Estrogen induces phosphorylation of cyclic AMP response element binding (pCREB) in primary hippocampal cells in a time-dependent manner

Lee, S.J; Campomanes, Claire R.; Sikat, P.T; Greenfield, Audrey T.; Allen, Patrick B.; McEwen, Bruce S.

doi:10.1016/j.neuroscience.2003.11.035

Cited by 114 publications

(84 citation statements)

References 53 publications

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“…Like αCaMKII, all three proteins are involved in neuronal differentiation, and ERK1/2 and CREB have also been shown to play a role in LTP and memory processes (Trifilieff, 2006). E2 action has previously been linked to ERK1/2 and CREB phosphorylation in various populations of neurons and in vivo (Lee, 2004;Bryant DN, 2005;Szego, 2006), and we have provided evidence that αCaMKII action mediates their phosphorylation by E2 in NLT and primary hippocampal neurons. CREB can be directly phosphorylated by αCaMKII (Wu, 2001), although in our studies it appears that CREB is indirectly affected by αCaMKII-mediated ERK1/2 activity since its phosphorylation by E2 was blocked by U0126 pre-treatment.…”

Section: Discussionsupporting

confidence: 51%

“…Furthermore, E2 has been reported to stimulate their activation in various populations of neurons (Lee, 2004;Szego, 2006), although the role of αCaMKII in this activation has not been thoroughly investigated. To examine the effect of E2-induced αCaMKII activity on ERK1/2 and CREB phosphorylation, NLT cells were either unstimulated or treated for 10 min with vehicle, E2, or E2 plus 30 min pretreatment with KN-62, ICI, Nifedipine, or U0126, a commonly used inhibitor of ERK1/2 activity.…”

Section: E2 Stimulates Erk1/2 and Creb Phosphorylation Via A Camkii-amentioning

confidence: 99%

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Modulation of αCaMKII signaling by rapid ERα action

et al. 2008

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The estrogen receptor (ER) subtypes, ERα and ERβ, modulate numerous signaling cascades in the brain to result in a variety of cell fates including neuronal differentiation. We report here that 17β-estradiol (E2) rapidly stimulates the autophosphorylation of α-Ca 2+ /calmodulin-dependent kinase II (αCaMKII) in immortalized NLT GnRH neurons, primary hippocampal neurons, and Cos7 cells cotransfected with ERα and αCaMKII. The E2-induced αCaMKII autophosphorylation is ERα-and Ca 2+ /calmodulin (CaM)-dependent. Interestingly, the hormone-dependent association of ERα with αCaMKII attenuates the positive effect of E2 on αCaMKII autophosphorylation, suggesting that ERα plays a complex role in modulating αCaMKII activity and may function to fine-tune αCaMKII-triggered signaling events. However, it appears as though the activating signal of E2 dominates the negative effect of ER since there is a clear, positive downstream response to E2-activated αCaMKII; pharmacological inhibitors and RNAi technology show that targets of ERα-mediated αCaMKII signaling include extracellular signal-regulated kinase 1/2 (ERK1/2), cAMP response elementbinding protein (CREB), and microtubule associated protein 2 (MAP2). These findings suggest a novel model for the modulation of αCaMKII signaling by ERα, which provides a molecular link as to how E2 might influence brain function.

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Section: Discussionsupporting

confidence: 51%

Section: E2 Stimulates Erk1/2 and Creb Phosphorylation Via A Camkii-amentioning

confidence: 99%

Modulation of αCaMKII signaling by rapid ERα action

et al. 2008

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“…Estrogen has been found previously to exert rapid effects upon the electrical responses (Gu et al, 1999), immediate early gene expression (Rudick and Woolley, 2003) and second messenger phosphorylation patterns of CA1 neurons (Kuroki et al, 2001;Abraham et al, 2003;Lee et al, 2004). A prior electrophysiological study had investigated whether sex differences may exist in rapid estrogen actions within the hippocampus and, as found here for pCREB, no sexual dimorphism was evident (Fugger et al, 2001).…”

Section: Absence Of Sex Differences In Rapid Estrogen Actions In the mentioning

confidence: 64%

“…The intracellular pathways mediating the effects of estrogen upon CREB phosphorylation in the hippocampus are currently under examination. Studies in vitro have shown that both the mitogen-activated protein kinase and calcium-calmodulin kinase pathways are likely to be upstream signaling pathways (Lee et al, 2004). However, it is curious that the phosphorylation of CREB in the CA1 hippocampus in vivo is critically dependent upon ER␤ (Abraham et al, 2003).…”

Section: Absence Of Sex Differences In Rapid Estrogen Actions In the mentioning

confidence: 99%

Major sex differences in non-genomic estrogen actions on intracellular signaling in mouse brain in vivo

Ábrahám

Herbison

2005

Neuroscience

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Abstract-Rapid effects of estrogen have now been identified throughout the brain but the extent to which these actions may be different in males and females is unknown. Previous work has shown that estrogen rapidly phosphorylates Ser 133 of cAMP responsive element binding protein (CREB) through a non-genomic mechanism. Using this indicator, we have examined here whether non-genomic estrogen actions occur in a sexually dimorphic manner within the adult brain. Male and female mice were gonadectomized and 3 weeks later treated with 17-␤-estradiol or vehicle for 1 h prior to perfusion fixation and subsequent CREB and phosphorylated CREB (pCREB) immunostaining of brain sections. The numbers of cells expressing CREB immunoreactivity were not altered by estrogen treatment or different in males and females in any of the brain regions examined. However, estrogen treatment significantly (P<0.05) increased pCREB-immunoreactive cell numbers in the medial preoptic area, ventrolateral division of the ventromedial nucleus, medial septum and CA1 region of the hippocampus of female mice. In contrast, estrogen increased pCREB levels in the medial septum and CA1 but not in the preoptic area or ventromedial nucleus of male mice. To evaluate the extent to which non-genomic estrogen actions may be sexually differentiated within a single neuronal phenotype, dual labeling immunocytochemistry was undertaken to evaluate the gonadotropin-releasing hormone ( A variety of neuronal circuits in the mammalian brain exhibit robust sex differences in structure and function (De Vries, 1990;Simerly, 2002). Hypothalamic regions such as the medial preoptic area (mPOA) and ventromedial nucleus (VMN) contain key sexually differentiated neuronal circuits responsible for controlling reproductive function (Pfaff et al., 1994;Flanagan-Cato, 2000;Simerly, 2002). For example, the GnRH neurons within the mPOA represent the final output neurons of the network involved in regulating gonadal function (Levine, 2003). Whereas estrogen stimulates a massive increment in GnRH secretion to induce ovulation in the female mammal, it has no similar effect in males (Herbison, 1998). In addition, clear sex differences have been observed in the effects of estrogen on networks involved in regulating male and female sexual behavior (Pfaff et al., 1994;Flanagan-Cato, 2000). Interestingly, these sexually differentiated actions of estrogen are not confined solely to circuits involved in the modulation of reproductive function but also exist within brain regions such as the hippocampus (Woolley, 2000;Leranth et al., 2003).The mechanisms underlying the sexually dimorphic effects of estrogen on brain function in the adult are unclear. As one possibility, estrogen may regulate different numbers or populations of cells within a specific brain region of males and females. This is likely to be the case for the sexually dimorphic nucleus of the preoptic area and the spinal nucleus of the bulbocavernosus in the rat (for review see Simerly, 2002) where major sex differences in neuronal n...

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“…Previous studies showed that CREB activation is associated with GDNF expression (Young et al, 1999;Lenhard et al, 2002), implying that CREB may participate in regulating GDNF expression as a transcriptional factor. Phosphorylation of CREB at serine-133 (Ser 133 ) within the kinase-inducible domain is critical for its function as a stimulusdependent transcriptional activator, and multiple kinases have been implicated as activators of CREB in neurons, including protein kinase C (PKC) (Roberson et al,1999), calmodulin kinase II (CaMKII) (Lee et al, 2004), extracellular signal-regulated kinase 1/2 (ERK1/2) (Schinelli et al, 2001), and serine/threonine kinase Akt (Brunet et al, 2001). Different extracellular stimuli may activate distinct signalings, which contribute to CREB phosphorylation and cellular responses.…”

Section: Introductionmentioning

confidence: 99%

An Analog of a Dipeptide-Like Structure of FK506 Increases Glial Cell Line-Derived Neurotrophic Factor Expression through cAMP Response Element-Binding Protein Activated by Heat Shock Protein 90/Akt Signaling Pathway

Cen¹,

Nitta²,

Ohya³

et al. 2006

J. Neurosci.

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Glial cell line-derived neurotrophic factor (GDNF) is an important neurotrophic factor that has therapeutic implications for neurodegenerative disorders. We previously showed that leucine-isoleucine (Leu-Ile), an analog of a dipeptide-like structure of FK506 (tacrolimus), induces GDNF expression both in vivo and in vitro. In this investigation, we sought to clarify the cellular mechanisms underlying the GDNF-inducing effect of this dipeptide. Leu-Ile transport was investigated using fluorescein isothiocyanate-Leu-Ile in cultured neurons, and the results showed the transmembrane mobility of this dipeptide. By liquid chromatography-mass spectrometry and quartz crystal microbalance assay, we identified heat shock cognate protein 70 as a protein binding specifically to Leu-Ile, and molecular modeling showed that the ATPase domain is the predicted binding site. Leu-Ile stimulated Akt phosphorylation, which was attenuated significantly by heat shock protein 90 (Hsp90) inhibitor geldanamycin (GA). Moreover, enhanced interaction between phosphorylated Akt and Hsp90 was detected by immunoprecipitation. Leu-Ile elicited an increase in cAMP response element binding protein (CREB) phosphorylation, which was inhibited by GA, indicating that CREB is a downstream target of Hsp90/Akt signaling. Leu-Ile elevated the levels of GDNF mRNA and protein expression, whereas inhibition of CREB blocked such effects. Leu-Ile promoted the binding activity of phosphorylated CREB with cAMP response element. These findings show that CREB plays a key role in transcriptional regulation of GDNF expression induced by Leu-Ile. In conclusion, Leu-Ile activates Hsp90/Akt/CREB signaling, which contributes to the upregulation of GDNF expression. It may represent a novel lead compound for the treatment of dopaminergic neurons or motoneuron diseases.

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Estrogen induces phosphorylation of cyclic AMP response element binding (pCREB) in primary hippocampal cells in a time-dependent manner

Cited by 114 publications

References 53 publications

Modulation of αCaMKII signaling by rapid ERα action

Modulation of αCaMKII signaling by rapid ERα action

Major sex differences in non-genomic estrogen actions on intracellular signaling in mouse brain in vivo

An Analog of a Dipeptide-Like Structure of FK506 Increases Glial Cell Line-Derived Neurotrophic Factor Expression through cAMP Response Element-Binding Protein Activated by Heat Shock Protein 90/Akt Signaling Pathway

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