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5-Hydroxytryptamine (5-HT) cellular sequestration during chronic exposure delays 5-HT3 receptor resensitization due
J Daniel Hothersall1, Amy Alexander1, Andrew J Samson1
1Medical Research Institute, University of Dundee, Dundee DD1 9SY, Scotland, United Kingdom.
The Journal of Biological Chemistry
|October 5, 2014
Summary
Chronic serotonin exposure down-regulates serotonin 5-HT3 receptors via a novel mechanism. Sequestered serotonin release prolongs receptor desensitization, impacting synaptic regulation.
Area of Science:
- Neuroscience
- Pharmacology
- Cell Biology
Background:
- Serotonergic synapses are regulated by serotonin (5-hydroxytryptamine, 5-HT).
- Elevated 5-HT levels typically down-regulate serotonin transporters and 5-HT receptors, including 5-HT3 receptors.
Purpose of the Study:
- To investigate the mechanism of 5-HT3 receptor down-regulation by chronic 5-HT exposure.
- To determine the role of serotonin transporter function and intracellular serotonin sequestration in this process.
Main Methods:
- Recombinant expression of 5-HT3 receptors in COS-7 cells.
- Measurement of 5-HT3 receptor binding and function (guinea pig ileum contractions).
- TX-114 extraction to assess 5-HT localization.
Main Results:
- Chronic 5-HT exposure reduced 5-HT3 receptor binding and function.
- Down-regulation was potentiated by serotonin transporter activity and correlated with 5-HT uptake.
- Intracellularly sequestered 5-HT was found to be releasable and sufficient to prevent receptor recovery.
Conclusions:
- A novel mechanism of 5-HT3 receptor down-regulation involves chronic release of sequestered 5-HT.
- This release prolongs receptor desensitization, independent of endocytosis or altered surface receptor levels.
- Findings suggest a new pathway for regulating serotonergic neurotransmission.
Keywords:
5-HT3IntestineIon ChannelMembrane TraffickingPharmacologyReceptor DesensitizationReceptor InternalizationSelective Serotonin Reuptake Inhibitor (SSRI)SerotoninSerotonin TransporterMore Related Videos
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