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Organic Cation Transporters and Nongenomic Glucocorticoid Action

Kelsey C Benton1, Christopher A Lowry2, Paul J Gasser3

  • 1Department of Biomedical Sciences, Marquette University, Milwaukee, WI, USA.

Handbook of Experimental Pharmacology
|June 9, 2021
PubMed

Insights

Corticosteroid hormones rapidly affect brain function by inhibiting the organic cation transporter 3 (OCT3), which clears monoamines. This action modulates neuronal and glial activity, influencing physiology and behavior through nongenomic pathways.

Area of Science:

  • Neuroendocrinology
  • Molecular Neuroscience
  • Cellular Physiology

Background:

  • Corticosteroid hormones (e.g., corticosterone) influence neuronal physiology and behavior via genomic and nongenomic mechanisms.
  • Genomic effects involve intracellular receptors (glucocorticoid receptors [GR] and mineralocorticoid receptors [MR]) altering gene expression.
  • Nongenomic mechanisms offer rapid effects distinct from slower genomic pathways.

Purpose of the Study:

  • To review evidence for corticosterone's rapid, nongenomic effects on the brain.
  • To explore the role of the organic cation transporter 3 (OCT3) in mediating these effects.
  • To examine the broader contributions of the "uptake2" transporter family to corticosteroid actions.

Main Methods:

  • Review of existing studies on OCT3 expression and function in the brain.
  • Analysis of corticosterone's interaction with monoamine transport systems.
  • Examination of corticosteroid sensitivity in "uptake2" family transporters.

Main Results:

  • Corticosterone directly inhibits monoamine transport mediated by OCT3, a high-capacity, low-affinity transporter.
  • OCT3 is expressed in the brain, facilitating the clearance of norepinephrine, epinephrine, dopamine, serotonin, and histamine.
  • Evidence supports the hypothesis that corticosterone modulates glia and neurons by inhibiting OCT3-mediated monoamine clearance.

Conclusions:

  • Corticosterone exerts rapid, nongenomic effects on brain function by inhibiting OCT3-mediated monoamine transport.
  • This mechanism provides a novel pathway for modulating neuronal and glial activity, impacting physiology and behavior.
  • Other "uptake2" family members may also contribute to the rapid, nongenomic actions of corticosteroids in the central nervous system.
Keywords:
CorticosteroneDopamineHistamineNorepinephrineOCT2OCT3Organic cation transporter 2Organic cation transporter 3SerotoninSolute carrier family 22 (organic cation transporter)slc22a3

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