# Investigating the trafficking mechanisms and signaling consequences of dopamine receptor primary cilia localization

> **NIH NIH F32** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2022 · $67,174

## Abstract

Project Summary/Abstract
Ciliopathies are genetic disorders that arise from cilia loss or dysfunctional signaling, characterized by a multitude
of defects, including neurological symptoms. A subset of G protein-coupled receptors (GPCRs) are enriched in
primary cilia, including receptors for the modulatory neurotransmitter, dopamine. Dopamine receptor (DR) cilia
localization was described a decade ago, yet the underlying cellular trafficking machinery remains largely
undefined. Interestingly, published work from our lab and others supports the hypothesis that the DR cilia
targeting mechanism is selective and distinct from other ciliary GPCRs. Moreover, the impact of cilia-specific DR
signaling on neuronal function and activity is largely unexplored.
This proposal aims to test two central hypotheses: (1) DR cilia trafficking is mechanistically distinct from the
prevailing understanding of GPCR cilia localization, and (2) DR signaling from the primary cilium impacts
neuronal cAMP downstream of dopaminergic stimulation. We will take a multifaceted approach in order to tackle
these questions using IMCD3 cells, an established ciliated cell culture model ideal for investigating the molecular
mechanisms underpinning GPCR cilia trafficking. First, we will elucidate and refine the DR sequence motifs
necessary and sufficient for cilia localization. We will then employ unbiased, quantitative proteomics to uncover
novel factors that bind directly to DRs, and are required for cilia localization. Next, we will test whether DR cilia
targeting requires a distinct subset of cilia transport machinery from other cilia-localized GPCRs using standard
biochemical and CRISPR/Cas9 gene editing techniques. Furthermore, this proposal will test the hypothesis that
the structural determinants and cilia trafficking proteins required for DR cilia trafficking in heterologous cells are
conserved in striatal medium spiny neurons, the endogenous DR context. Finally, we will examine the
downstream consequences of cilia-specific DR activation, focusing on cAMP, in striatal neurons. The proposed
experiments will greatly expand our understanding of selective ciliary trafficking mechanisms, and be the first to
examine the impact of localized DR signaling from primary cilia in neurons. In addition, the training plan and
institutional support detailed in this proposal provide exceptional tools for advancing the applicant towards a
career as an independent scientist.

## Key facts

- **NIH application ID:** 10464628
- **Project number:** 1F32MH130096-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Rita Reale Fagan
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $67,174
- **Award type:** 1
- **Project period:** 2022-05-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10464628

## Citation

> US National Institutes of Health, RePORTER application 10464628, Investigating the trafficking mechanisms and signaling consequences of dopamine receptor primary cilia localization (1F32MH130096-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10464628. Licensed CC0.

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