# Signaling Pathways that Modulate Neuronal Activity

> **NIH NS R01** · FRED HUTCHINSON CANCER CENTER · 2026 · $512,963

## Abstract

Project summary
G protein-coupled receptor kinases (GRKs) play a pivotal role in modulating neuromodulatory signals by altering
GPCRs, with implications for a range of neurological and psychiatric conditions that affect sensation, mood, and
movement. The inherent complexity of the GRK protein family, characterized by several similar paralogs and the
broad regulation of numerous GPCRs, presents a significant challenge in delineating their functions in vivo. Our
research in the nematode Caenorhabditis elegans which has only two GRK paralogs (GRK-1 and GRK-2) has
brought to light novel mechanisms of GRK function and specificity. In particular, our studies have found that mutants
of grk-2 exhibit impaired exploration behavior. We also found that loss of either the SSU-1 sulfotransferase or the
FLP-1 neuropeptide partially mitigates these impairments, and the concurrent loss of both SSU-1 and FLP-1 fully
restores normal exploration behavior in grk-2 mutants, revealing an unexpected level of functional specificity in
GRK-mediated signaling in vivo. Based on these insights, our proposed research has three main objectives. First,
we will determine how GRK-2 interacts with the SSU-1 sulfotransferase pathway in sensory neurons to regulate
exploratory locomotion. Second, we will decode the network mechanisms through which GRK-2 signaling in sensory
neurons can regulate FLP-1 neuropeptide secretion from AVK interneurons, despite lacking direct synaptic
connections. Third, we will elucidate the cooperative and independent roles of the distinct GRK paralogs GRK-1 and
GRK-2 in modulating neuronal communication and behavior by studying their structural features, expression
patterns, and behavioral impacts. Our comprehensive studies aim to unravel the intricate mechanisms of GRK
regulation in regulating neuronal function and behavior.

## Key facts

- **NIH application ID:** 11322744
- **Project number:** 5R01NS109476-06
- **Recipient organization:** FRED HUTCHINSON CANCER CENTER
- **Principal Investigator:** Michael  Ailion; Jihong  Bai
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NS
- **Fiscal year:** 2026
- **Award amount:** $512,963
- **Award type:** 5
- **Project period:** 2020-01-01T00:00:00 → 2030-03-31T00:00:00

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11322744

## Citation

> US National Institutes of Health, RePORTER application 11322744, Signaling Pathways that Modulate Neuronal Activity (5R01NS109476-06). Retrieved via AI Analytics 2026-07-05 from https://api.ai-analytics.org/grant/nih/11322744. Licensed CC0.

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