Author ORCID Identifier
https://orcid.org/0000-0001-9813-0978
Defense Date
2024
Document Type
Thesis
Degree Name
Master of Science
Department
Pharmacology & Toxicology
First Advisor
Sammanda Ramamoorthy
Abstract
Rationale: Serotonin (5-HT) is a crucial neurotransmitter involved in regulating various physiological processes. Dysregulation of the serotonergic system has been implicated in several neuropsychiatric disorders. Though numerous 5-HT receptors exist, the 5-HT transporter (SERT) is responsible for 5-HT clearance in the brain and periphery. 5-HT1Bautoreceptors regulate 5-HT release and interact with glycogen synthase kinase-3β (GSK3β), which can modulate SERT function via specific Ser44/48 phosphorylation sites. While these findings suggest a potential interplay between 5-HT1Band GSK3β-mediated SERT phosphorylation in regulating extracellular 5-HT, the primary causal molecular link remains unknown.
Objectives: To investigate if 5-HT1B activation by the agonist CP-94253 influences SERT-mediated 5-HT clearance through GSK3β-dependent - SERT-Ser44/48 phosphorylation, and to examine regional and sex differences.
Methods: 5-HT uptake assay and kinetic analysis performed with region-specific crude synaptosomes from female wild-type mice and SERT-A44/A48 knock-in mice, following CP-94253 treatment.
Results: In wild-type female mice, CP-94253 treatment showed a non-significant enhancement of SERT-mediated 5-HT uptake in the striatum and hippocampus. Kinetic analyses revealed a significant increase in the Vmax of 5-HT uptake in the hippocampus. However, SERT S44A/S48A knock-in mice exhibited elevated SERT-mediated uptake even without treatment, and CP-94253 did not further increase uptake in these mice, suggesting the importance of these phosphorylation sites.
Conclusions: The loss of CP-94253-induced changes in uptake kinetics in the SERT S44A/S48A knock-in mice, in both the striatum and hippocampus, reinforces the critical role of these SERT phosphorylation sites in mediating the 5-HT1B receptor-GSK3β regulation of SERT function and 5-HT reuptake dynamics.
Rights
© Sanyukta Jalihalkar
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
8-8-2024