Related Experiment Video
Updated: Jun 28, 2026
07:16
Methods for the Discovery of Novel Compounds Modulating a Gamma-Aminobutyric Acid Receptor Type A Neurotransmission
Published on: August 16, 2018
Valproic acid regulates catecholaminergic pathways by concentration-dependent threshold effects on TH mRNA synthesis
Antoni D'Souza1, Eylem Onem, Pranav Patel
1Division of Newborn Medicine, Department of Pediatrics, New York Medical College, Valhalla, New York 10595, USA.
Brain Research
|November 4, 2008
Summary
Valproic acid (VPA) regulates tyrosine hydroxylase (TH) gene expression, impacting catecholamine pathways. This VPA action may explain its therapeutic effects in neurological and psychiatric disorders.
Area of Science:
- Neuroscience
- Pharmacology
- Molecular Biology
Background:
- Valproic acid (VPA) is clinically used for neurological and psychiatric disorders, but its mechanisms of action are not fully understood.
- Noradrenergic systems and tyrosine hydroxylase (TH) expression are implicated in mood disorders.
- Previous studies showed sodium butyrate (SB) affects TH gene expression.
Purpose of the Study:
- To investigate if valproic acid (VPA) regulates tyrosine hydroxylase (TH) gene expression in vitro.
- To determine the concentration-dependent effects of VPA on TH mRNA and protein levels.
Main Methods:
- In vitro study using PC12 cells.
- Analysis of TH gene transcription and mRNA stability.
- Mutagenesis of TH promoter elements (cAMP- and butyrate-response elements).
- Co-expression of dominant-negative CREB forms.
Main Results:
- VPA induced TH transcription similarly to SB.
- VPA-stimulated transcription was reduced by promoter mutations or dominant-negative CREB.
- Low VPA concentrations (0.1 mM) increased TH mRNA and protein, while higher concentrations (>0.5 mM) attenuated them.
- Concentration-dependent effects suggest regulation at the TH mRNA stability level.
Conclusions:
- Valproic acid (VPA) regulates TH gene expression and protein levels.
- VPA's therapeutic efficacy may be linked to its modulation of catecholaminergic pathways via TH regulation.
- A novel regulatory mechanism involving TH mRNA stability influenced by VPA concentration was identified.
Related Concept Videos
01:29Drugs Affecting Neurotransmitter Synthesis
Drugs affecting neurotransmitter synthesis can impact the adrenergic neuron and the synthesis of neurotransmitters. For example, α-methyltyrosine and carbidopa target specific enzymes involved in catecholamine synthesis. α-methyltyrosine inhibits the enzyme tyrosine hydroxylase, which converts tyrosine into dopamine. By blocking this enzyme, α-methyltyrosine reduces dopamine production and other catecholamines. Carbidopa, on the other hand, inhibits the enzyme dopa decarboxylase, which converts...
01:21Drugs Affecting Neurotransmitter Release or Uptake
Certain drugs can affect how neurotransmitters called catecholamines, are released or taken back up in the adrenergic neuron. They can have different effects on the body's sympathetic transmission. Reserpine, a natural compound found in the Rauwolfia shrub, blocks a transporter called vesicular monoamine transporter (VMAT), which leads to a buildup of catecholamines in the cell and reduces sympathetic transmission. Another drug called guanethidine works in multiple ways, including blocking...
01:25Adrenergic Agonists: Indirect-Acting Agents
Indirect-acting adrenergic agonists potentiate the effects of endogenous catecholamines through different mechanisms without directly binding to adrenoceptors.
One mechanism involves depleting stored catecholamines by displacing them from synaptic vesicles. These agents, known as "displacers," are transported into vesicles at the expense of noradrenaline. Examples include amphetamine and tyramine, which lack a catechol moiety, resulting in prolonged action, improved oral bioavailability, and...
One mechanism involves depleting stored catecholamines by displacing them from synaptic vesicles. These agents, known as "displacers," are transported into vesicles at the expense of noradrenaline. Examples include amphetamine and tyramine, which lack a catechol moiety, resulting in prolonged action, improved oral bioavailability, and...
01:09GPCRs Regulate Adenylyl Cylase Activity
Some GPCRs transmit signals through adenylyl cyclase (AC), a transmembrane enzyme. AC helps synthesize second messenger cyclic adenosine monophosphate (cAMP). AC catalyzes cyclization reaction and converts ATP to cAMP by releasing a pyrophosphate. The pyrophosphate is further hydrolyzed to phosphate by the enzyme pyrophosphatase, which drives cAMP synthesis to completion. However, cAMP is rapidly degraded to 5′ AMP by the enzymes phosphodiesterase (PDE), preventing overstimulation of cells.
Two...
Two...
01:20Desensitization and Tachyphylaxis
Tachyphylaxis is described as a rapid decrease in response to a drug after repeated or continuous administration of the same drug dose. It is a phenomenon where the body becomes less responsive to a particular substance or intervention over time, requiring higher doses or stronger interventions to achieve the same effect. It results from adaptive changes in the body's receptors, signaling pathways, or physiological processes that occur in response to prolonged exposure to a stimulus.
Several...
Several...
01:26Neurochemical Transmission: Sites of Drug Action
Neurochemical transmission, the conduction of electrical impulses between neurons mediated by neurotransmitters, plays a vital role in various physiological processes. Autonomic drugs exert their effects by modulating neurotransmission within the autonomic nervous system. For instance, drugs such as hemicholinium block the precursor uptake necessary for synthesizing acetylcholine, an essential autonomic neurotransmitter. Following synthesis, neurotransmitters are stored in vesicles. Metyrosine...