Limits...
Ethanol regulation of serum glucocorticoid kinase 1 expression in DBA2/J mouse prefrontal cortex.

Costin BN, Dever SM, Miles MF - PLoS ONE (2013)

Bottom Line: Three separate results suggested that ethanol regulated Sgk1 via circulating glucocorticoids: acute ethanol increased glucocorticoid receptor binding to the Sgk1 promoter; adrenalectomy blocked ethanol induction of Sgk1 mRNA; and chronic ethanol exposure during locomotor sensitization down-regulated HPA axis activation and Sgk1 induction by acute ethanol.Chronic ethanol modifies both SGK1 protein and HPA-mediated induction of Sgk1 mRNA.These adaptive molecular responses of glucocorticoid-responsive gene expression and SGK1 in prefrontal cortex may contribute to mechanisms underlying behavioral responses to chronic ethanol exposure.

View Article: PubMed Central - PubMed

Affiliation: Virginia Commonwealth University Alcohol Research Center, Virginia Commonwealth University, Richmond, Virginia, USA.

ABSTRACT

Background: We previously identified a group of glucocorticoid-responsive genes, including Serum Glucocorticoid kinase 1 (Sgk1), regulated by acute ethanol in prefrontal cortex of DBA2/J mice. Acute ethanol activates the hypothalamic pituitary adrenal axis (HPA) causing release of glucocorticoids. Chronic ethanol dysregulates the HPA response in both humans and rodents, possibly contributing to important interactions between stress and alcoholism. Because Sgk1 regulates ion channels and learning and memory, we hypothesized that Sgk1 contributes to HPA-dependent acute and adaptive neuronal responses to ethanol. These studies characterized acute and chronic ethanol regulation of Sgk1 mRNA and protein and their relationship with ethanol actions on the HPA axis.

Results: Acute ethanol increased Sgk1 mRNA expression in a dose and time dependent manner. Three separate results suggested that ethanol regulated Sgk1 via circulating glucocorticoids: acute ethanol increased glucocorticoid receptor binding to the Sgk1 promoter; adrenalectomy blocked ethanol induction of Sgk1 mRNA; and chronic ethanol exposure during locomotor sensitization down-regulated HPA axis activation and Sgk1 induction by acute ethanol. SGK1 protein had complex temporal responses to acute ethanol with rapid and transient increases in Ser422 phosphorylation at 15 min. following ethanol administration. This activating phosphorylation had functional consequences, as suggested by increased phosphorylation of the known SGK1 target, N-myc downstream-regulated gene 1 (NDRG1). After repeated ethanol administration during locomotor sensitization, basal SGK1 protein phosphorylation increased despite blunting of Sgk1 mRNA induction by ethanol.

Conclusions: These results suggest that HPA axis and glucocorticoid receptor signaling mediate acute ethanol induction of Sgk1 transcription in mouse prefrontal cortex. However, acute ethanol also causes complex changes in SGK1 protein expression and activity. Chronic ethanol modifies both SGK1 protein and HPA-mediated induction of Sgk1 mRNA. These adaptive molecular responses of glucocorticoid-responsive gene expression and SGK1 in prefrontal cortex may contribute to mechanisms underlying behavioral responses to chronic ethanol exposure.

Show MeSH

Related in: MedlinePlus

Effects of adrenalectomy on Sgk1 induction following ethanol administration.(a) Q-rtPCR analysis of Sgk1 in saline and ethanol treated SHAM versus ADX animals. * p < 0.05 versus saline treated SHAM animals and saline and ethanol treated ADX animals; (b) Corticosterone levels 1hour following acute ethanol administration. * p < 0.05 versus saline treated SHAM animals and saline and ethanol treated ADX animals.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3750005&req=5

pone-0072979-g005: Effects of adrenalectomy on Sgk1 induction following ethanol administration.(a) Q-rtPCR analysis of Sgk1 in saline and ethanol treated SHAM versus ADX animals. * p < 0.05 versus saline treated SHAM animals and saline and ethanol treated ADX animals; (b) Corticosterone levels 1hour following acute ethanol administration. * p < 0.05 versus saline treated SHAM animals and saline and ethanol treated ADX animals.

Mentions: Because Sgk1 was not induced in EE treated animals and the corticosterone response to ethanol was also blunted in these animals, we hypothesized that Sgk1 would not be induced in ADX animals, animals lacking their adrenal glands, the organ responsible for corticosterone release and the final step in HPA axis activation. Q-rtPCR analysis of Sgk1 mRNA levels at 4 hours following ethanol (4 g/kg i.p.) showed an overall effect (two-way ANOVA, phenotype x treatment) of phenotype (F1,22= 7.16, p < 0.05), treatment (F1,22= 11.05, p < 0.01) and a significant (phenotype x treatment) interaction (F1,22= 5.31, p < 0.05) (Figure 5a). Post-hoc analysis of phenotype indicated Sgk1 levels were significantly increased in ethanol versus saline treated Sham animals, but not ADX animals. Post-hoc analysis of treatment indicated significant differences between ethanol, but not saline, treated Sham versus ADX mice indicating that Sgk1 levels were blunted in ADX mice following ethanol administration. We also evaluated Sgk1.1 (Figure S3) and found no differences between Sgk1.1 levels in ADX versus Sham treated or saline versus ethanol treated animals.


Ethanol regulation of serum glucocorticoid kinase 1 expression in DBA2/J mouse prefrontal cortex.

Costin BN, Dever SM, Miles MF - PLoS ONE (2013)

Effects of adrenalectomy on Sgk1 induction following ethanol administration.(a) Q-rtPCR analysis of Sgk1 in saline and ethanol treated SHAM versus ADX animals. * p < 0.05 versus saline treated SHAM animals and saline and ethanol treated ADX animals; (b) Corticosterone levels 1hour following acute ethanol administration. * p < 0.05 versus saline treated SHAM animals and saline and ethanol treated ADX animals.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3750005&req=5

pone-0072979-g005: Effects of adrenalectomy on Sgk1 induction following ethanol administration.(a) Q-rtPCR analysis of Sgk1 in saline and ethanol treated SHAM versus ADX animals. * p < 0.05 versus saline treated SHAM animals and saline and ethanol treated ADX animals; (b) Corticosterone levels 1hour following acute ethanol administration. * p < 0.05 versus saline treated SHAM animals and saline and ethanol treated ADX animals.
Mentions: Because Sgk1 was not induced in EE treated animals and the corticosterone response to ethanol was also blunted in these animals, we hypothesized that Sgk1 would not be induced in ADX animals, animals lacking their adrenal glands, the organ responsible for corticosterone release and the final step in HPA axis activation. Q-rtPCR analysis of Sgk1 mRNA levels at 4 hours following ethanol (4 g/kg i.p.) showed an overall effect (two-way ANOVA, phenotype x treatment) of phenotype (F1,22= 7.16, p < 0.05), treatment (F1,22= 11.05, p < 0.01) and a significant (phenotype x treatment) interaction (F1,22= 5.31, p < 0.05) (Figure 5a). Post-hoc analysis of phenotype indicated Sgk1 levels were significantly increased in ethanol versus saline treated Sham animals, but not ADX animals. Post-hoc analysis of treatment indicated significant differences between ethanol, but not saline, treated Sham versus ADX mice indicating that Sgk1 levels were blunted in ADX mice following ethanol administration. We also evaluated Sgk1.1 (Figure S3) and found no differences between Sgk1.1 levels in ADX versus Sham treated or saline versus ethanol treated animals.

Bottom Line: Three separate results suggested that ethanol regulated Sgk1 via circulating glucocorticoids: acute ethanol increased glucocorticoid receptor binding to the Sgk1 promoter; adrenalectomy blocked ethanol induction of Sgk1 mRNA; and chronic ethanol exposure during locomotor sensitization down-regulated HPA axis activation and Sgk1 induction by acute ethanol.Chronic ethanol modifies both SGK1 protein and HPA-mediated induction of Sgk1 mRNA.These adaptive molecular responses of glucocorticoid-responsive gene expression and SGK1 in prefrontal cortex may contribute to mechanisms underlying behavioral responses to chronic ethanol exposure.

View Article: PubMed Central - PubMed

Affiliation: Virginia Commonwealth University Alcohol Research Center, Virginia Commonwealth University, Richmond, Virginia, USA.

ABSTRACT

Background: We previously identified a group of glucocorticoid-responsive genes, including Serum Glucocorticoid kinase 1 (Sgk1), regulated by acute ethanol in prefrontal cortex of DBA2/J mice. Acute ethanol activates the hypothalamic pituitary adrenal axis (HPA) causing release of glucocorticoids. Chronic ethanol dysregulates the HPA response in both humans and rodents, possibly contributing to important interactions between stress and alcoholism. Because Sgk1 regulates ion channels and learning and memory, we hypothesized that Sgk1 contributes to HPA-dependent acute and adaptive neuronal responses to ethanol. These studies characterized acute and chronic ethanol regulation of Sgk1 mRNA and protein and their relationship with ethanol actions on the HPA axis.

Results: Acute ethanol increased Sgk1 mRNA expression in a dose and time dependent manner. Three separate results suggested that ethanol regulated Sgk1 via circulating glucocorticoids: acute ethanol increased glucocorticoid receptor binding to the Sgk1 promoter; adrenalectomy blocked ethanol induction of Sgk1 mRNA; and chronic ethanol exposure during locomotor sensitization down-regulated HPA axis activation and Sgk1 induction by acute ethanol. SGK1 protein had complex temporal responses to acute ethanol with rapid and transient increases in Ser422 phosphorylation at 15 min. following ethanol administration. This activating phosphorylation had functional consequences, as suggested by increased phosphorylation of the known SGK1 target, N-myc downstream-regulated gene 1 (NDRG1). After repeated ethanol administration during locomotor sensitization, basal SGK1 protein phosphorylation increased despite blunting of Sgk1 mRNA induction by ethanol.

Conclusions: These results suggest that HPA axis and glucocorticoid receptor signaling mediate acute ethanol induction of Sgk1 transcription in mouse prefrontal cortex. However, acute ethanol also causes complex changes in SGK1 protein expression and activity. Chronic ethanol modifies both SGK1 protein and HPA-mediated induction of Sgk1 mRNA. These adaptive molecular responses of glucocorticoid-responsive gene expression and SGK1 in prefrontal cortex may contribute to mechanisms underlying behavioral responses to chronic ethanol exposure.

Show MeSH
Related in: MedlinePlus