# Trafficking properties of the serotonin receptor variants

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2024 · $190,518

## Abstract

Project summary:
Serotonin, or 5 hydroxytryptamine (5HT) is an endogenous transmitter that is broadly implicated in many
modalities of human behavior including mood, libido, appetite and sleep, as well as peripheral functions in platelet
aggregation, immune response and bone density. In the brain, this single transmitter binds and activates seven
different families of 5HT receptors with five distinct modes of signal transduction, including all four classes of G
protein-coupled receptor (GPCR) (Gi, Gs, Gq and G12/13) and a ligand-gated ion channel. Alterations in the relative
balance of these diverse signaling pathways by 5HT has been implicated in a plethora of syndromes including
depression, major depressive disorder, bipolar disorder, schizophrenia, obsessive compulsive disorder and
attention deficit hyperactivity disorder. Selective serotonin reuptake inhibitors (SSRIs) are widely prescribed for
the treatment of depression, and more than 15% of adults in the US have taken an antidepressant within the
past 12 months. In theory, the efficacy of these drugs is due to their ability to increase 5HT levels by blocking
reuptake of 5HT. However, while these drugs increase 5HT levels in as little as 2 hours, it takes 4-8 weeks for
them to become effective at ameliorating depression. This suggests that the mechanism of action of SSRIs is
more complicated than simple increases in transmitter levels. We hypothesize that high levels of 5HT, produced
through use of SSRIs, can, in time, rebalance the expression levels of the various 5HT receptors and, by doing
so, provide therapeutic benefit. Specifically, we propose that some of the 5HTRs, when activated by 5HT,
undergo endocytosis and recycling/resensitization while others are endocytosed and degraded in the lysosome.
The high levels of 5HT provided by the SSRI can, thereby, drive down expression of certain subtypes of 5HTR,
while maintaining a high level of signaling through others--in effect “rebalancing” 5HT signal transduction to more
closely resemble the non-depressed state. Here, we will perform a comprehensive analysis of the endocytic and
post-endocytic properties of the entire family of 5HTRs. Remarkably, there is very limited knowledge regarding
the post-endocytic sorting properties of the 5HTRs. Hence, regardless of outcome, these data will provide new
information regarding how increased 5HT levels, due to SSRIs, could alter receptor expression and could inform
new approaches to serotonin therapeutics designed to rebalance 5HT signal transduction.

## Key facts

- **NIH application ID:** 10894153
- **Project number:** 5R21DA058216-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** JENNIFER L WHISTLER
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $190,518
- **Award type:** 5
- **Project period:** 2023-08-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10894153

## Citation

> US National Institutes of Health, RePORTER application 10894153, Trafficking properties of the serotonin receptor variants (5R21DA058216-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10894153. Licensed CC0.

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