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Related Concept Videos

Drugs Affecting Neurotransmitter Release or Uptake01:21

Drugs 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...
Drugs Affecting Neurotransmitter Synthesis01:29

Drugs 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...
Adrenergic Agonists: Indirect-Acting Agents01:25

Adrenergic 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...
Neurochemical Transmission: Sites of Drug Action01:26

Neurochemical 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...
Desensitization and Tachyphylaxis01:20

Desensitization 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...
Adrenergic Neurons: Neurotransmission01:27

Adrenergic Neurons: Neurotransmission

Postganglionic sympathetic fibers (except those supplying the sweat glands) releasing noradrenaline or norepinephrine are called noradrenergic or adrenergic neurons. Noradrenaline, dopamine, adrenaline, or epinephrine are collectively called "catecholamines" as they contain a catechol moiety and an amine side chain. The five stages of neurotransmitter release involve their synthesis, storage, release, reuptake and metabolism.
Synthesis: Catecholamine synthesis requires tyrosine, which is taken...

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Method for Identifying Small Molecule Inhibitors of the Protein-protein Interaction Between HCN1 and TRIP8b
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Cytokines inhibit norepinephrine transporter expression by decreasing Hand2.

Michael J Pellegrino1, Diana C Parrish, Richard E Zigmond

  • 1Department of Physiology and Pharmacology, Oregon Health & Science University, Portland, OR 97239, USA.

Molecular and Cellular Neurosciences
|January 19, 2011
PubMed
Summary

Inflammatory cytokines suppress noradrenergic function by reducing Hand2 or Gata3 transcription factors, which are crucial for norepinephrine transporter (NET) expression in sympathetic neurons. Nerve injury selectively downregulates Hand2.

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Area of Science:

  • Neuroscience
  • Molecular Biology
  • Cell Biology

Background:

  • Noradrenergic transmission relies on norepinephrine (NE) synthesis and reuptake via the norepinephrine transporter (NET).
  • Inflammatory cytokines, via gp130 signaling, can suppress the noradrenergic phenotype in sympathetic neurons, particularly after injury or during development.
  • The molecular mechanisms underlying cytokine-induced suppression of noradrenergic gene expression, including NET, are not fully understood.

Purpose of the Study:

  • To investigate the role of transcription factors in cytokine-mediated suppression of norepinephrine transporter (NET) gene transcription in sympathetic neurons.
  • To determine if Phox2a, Hand2, or Gata3 are involved in the suppression of NET by inflammatory cytokines.

Main Methods:

  • Utilized sympathetic neurons and neuroblastoma cells to study cytokine effects on NET transcription.
  • Performed chromatin immunoprecipitation to assess Phox2a binding to the NET promoter.
  • Overexpressed transcription factors (Phox2a, Hand2, Gata3) to evaluate their impact on NET expression.
  • Analyzed mRNA levels of NET, Hand2, and Gata3 in sympathetic neurons following axotomy.

Main Results:

  • Phox2a did not bind the NET promoter and its overexpression did not prevent cytokine suppression of NET transcription.
  • Cytokines decreased both Hand2 and Gata3 expression in sympathetic neurons and neuroblastoma cells.
  • Overexpression of either Hand2 or Gata3 rescued NET transcription suppressed by cytokines.
  • Axotomy in adult animals led to decreased NET and Hand2 mRNA levels, while Gata3 mRNA remained unchanged.

Conclusions:

  • Cytokines inhibit NET expression in cultured sympathetic neurons primarily through the downregulation of Hand2 or Gata3.
  • Axotomy in adult sympathetic neurons selectively suppresses Hand2 expression, suggesting distinct mechanisms of noradrenergic gene regulation following injury.
  • Hand2 and Gata3 are key regulators of NET transcription suppressed by inflammatory signals.