Abstract
Valproic acid (VPA) has been widely used in clinics for the treatment of multiple neuropsychiatric disorders, such as epilepsy and bipolar disorder. One of the mechanisms by which VPA exerts its effect is through regulating the brain levels of serotonin. However, the molecular basis of this VPA action is not fully understood. Here, we report for the first time that VPA activates monoamine oxidase (MAO) A catalytic activity, mRNA level, and promoter activity. MAO A is a key enzyme that degrades a number of monoamine neurotransmitters, including serotonin. Our results show that VPA increased the phosphorylation of both Akt and Forkhead box O1 (FoxO1), whereas pretreatment of cells with 2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride (LY294002) (a phosphoinositide 3-kinase inhibitor) reduced the VPA activation of MAO A. Overexpression of FoxO1 dramatically repressed both the basal and VPA-induced MAO A catalytic and promoter activities to 30 to 60%. Small interfering RNA knockdown of FoxO1 attenuated the stimulating effect of VPA on MAO A. Moreover, introduction of a constitutively active form of FoxO1 abolished the activation of MAO A by VPA and Akt. These results suggest that FoxO1 is a repressor for MAO A transcription, and its phosphorylation is involved in VPA activation of MAO A. Sequence analysis, electrophoretic mobility shift and chromatin immunoprecipitation assays further showed the presence of a functional FoxO1-binding site in MAO A core promoter. Taken together, these results demonstrate that MAO A is a novel target for VPA via Akt/FoxO1 signaling pathway. This information provides new insights into the pharmacological mechanisms and therapeutic implications of VPA action.
Footnotes
↵ The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.
This work was supported by the National Institutes of Health National Institute of Mental Health [Grants R01MH67968, R01MH39085]; and the Boyd and Elsie Welin Professorship.
Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
doi:10.1124/mol.111.072744.
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ABBREVIATIONS:
- VPA
- valproic acid
- 5-HT
- 5-hydroxytryptamine/serotonin
- AAA
- constitutively active
- CA
- constitutively active
- DA
- dopamine
- FoxO1
- Forkhead box O1
- HDAC
- histone deacetylase
- luc
- luciferase
- MAO
- monoamine oxidase
- NE
- norepinephrine
- PI3K
- phosphoinositide 3-kinase
- WT
- wild type
- LY294002
- 2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride
- DMSO
- dimethyl sulfoxide
- siRNA
- small interfering RNA
- PCR
- polymerase chain reaction
- RT-PCR
- reverse transcription-polymerase chain reaction
- qPCR
- quantitative polymerase chain reaction
- IP
- immunoprecipitate
- NS
- nonspecific
- FVS
- fetal valproate syndrome
- E18
- embryonic day 18.
- Received April 4, 2011.
- Accepted July 20, 2011.
- Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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