# Regulation of Serotonin Transporters

> **NIH NIH R01** · FLORIDA ATLANTIC UNIVERSITY · 2021 · $459,910

## Abstract

The presynaptic, antidepressant-sensitive serotonin (5-HT) transporter (SERT) is the major mechanism for 5-HT inactivation and recycling in the brain and periphery. In accord with its powerful control over 5-HT signaling
and homeostasis, SERT synthesis, trafficking and activity are highly regulated by multiple signaling pathways.
Alterations in SERT expression, function or regulation have been implicated in multiple neuropsychiatric disorders, including depression, anxiety, obsessive-compulsive disorder, and autism, though much evidence is indirect, owing in large part to a lack of opportunities to dissect SERT regulation and dysregulation in vivo. Over
the last period of support for this project, we demonstrated that an inflammatory cytokine pathway linked to IL-1R/p33α MAPK activation rapidly translates immune system activation to elevated SERT activity, increased 5-HT clearance and altered behavior. Remarkably, this pathway appears to be unable to modulate activity of
several autism-associated SERT coding variants, including the hyperfunctional variant Ala56, supporting the
idea that a dual analysis of both heritable SERT mutations and cytokine-triggered regulatory pathways can
advance our understanding of both fundamental SERT regulation and the networks that drive maladaptive
SERT states associated with mental illness. We hypothesize that SERT Ala56 constitutively imposes “outward-
facing” conformations (SERT*) that are normally occupied transiently during the course of normal, presynaptic
IL-1R/p38 MAPK regulation. Furthermore, we propose that stabilization of SERT* by the Ala56 mutation
throughout life drives disease-associated changes in 5-HT signaling and, more pertinent to the current proposal, provides a unique opportunity to capture transient molecular alterations, interactions and functional
states that are otherwise difficult to study. In pursuit of this idea, we generated SERT Ala56 KI mice, and have
demonstrated that these animals display autism-like behavioral features, as well as biochemical and functional
changes consistent with constitutive IL-1R/p38 MAPK stimulation. To dissect the requirements for immune activation pathways that normally activate wildtype SERT and that contribute to the constitutive hyperactivity of
SERT Ala56, we generated mice that afford conditional suppression of either p38α MAPK or its upstream activator, the IL-1R. We also generated mice that prevent or mimic phosphorylation at a key site linked to SERT
conformational stabilization and trafficking-independent SERT stimulation. Finally, we appropriate a newly developed, CNS penetrant and isoform-selective, p38α MAPK antagonist, whose use can bypass the potential
confounds of developmental p38α MAPK deletion. With these tools we interrogate changes in native SERT
phosphorylation states, SERT interacting proteins (SIPs), and functional states, clarifying the relationship between SERT* states of SERT Ala56 and immune-activated transporters. Altogether, our...

## Key facts

- **NIH application ID:** 10222488
- **Project number:** 5R01MH094527-29
- **Recipient organization:** FLORIDA ATLANTIC UNIVERSITY
- **Principal Investigator:** Randy D. Blakely
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $459,910
- **Award type:** 5
- **Project period:** 1994-08-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10222488

## Citation

> US National Institutes of Health, RePORTER application 10222488, Regulation of Serotonin Transporters (5R01MH094527-29). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10222488. Licensed CC0.

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