Distinct receptors for a promiscuous RFamide neuropeptide co-regulate a distributed circuit for locomotory arousal in C. elegans
Abstract
Neuropeptides modulate brain function by acting as ligands for a wide range of receptors. Systematic pharmacological screening efforts revealed extensive promiscuity in peptide-receptor pairs. However, the endogenous receptors and functions of promiscuous neuropeptides remain poorly understood. Here, we investigated how the Caenorhabditis elegans promiscuous RFamide-peptide FLP-14 and its receptors modulate a circuit for O2-evoked locomotory arousal. We show that FLP-14 peptides released from O2-sensing neurons and interneurons attenuate O2-evoked arousal by acting on 3 phylogenetically diverse G protein-coupled receptors (DMSR-3, FRPR-8, and NPR-40). Loss of each receptor individually confers strong hyperarousal by O2 comparable to the loss of flp-14. Distinct FLP-14 receptors have nonredundant roles in different target cells, including RID and RIM interneurons, that correlate antagonistically with locomotory arousal. Our results show that FLP-14 signaling requires coordinated modulation of multiple circuit nodes through distinct receptors in attenuating O2-evoked arousal. This promiscuous RFamide peptide network is reminiscent of monoaminergic neuromodulatory networks, which shape behavior through multiple receptors that differentially regulate distributed target neurons.
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BibTeX
@article{fruyt2026distinct,
title = {{Distinct receptors for a promiscuous RFamide neuropeptide co-regulate a distributed circuit for locomotory arousal in C. elegans}},
author = {Nathan De Fruyt and Aleksandra Chudinova and Saurabh Thapliyal and Ellen Geens and Charline Roy and Elke Vandewyer and Sara Van Damme and Lucas Mergan and Isabel Beets},
journal = {Genetics},
year = {2026},
month = jul,
doi = {10.1093/genetics/iyag188},
url = {https://doi.org/10.1093/genetics/iyag188},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Distinct receptors for a promiscuous RFamide neuropeptide co-regulate a distributed circuit for locomotory arousal in C. elegans
AU - Nathan De Fruyt
AU - Aleksandra Chudinova
AU - Saurabh Thapliyal
AU - Ellen Geens
AU - Charline Roy
AU - Elke Vandewyer
AU - Sara Van Damme
AU - Lucas Mergan
AU - Isabel Beets
PY - 2026
DA - 2026/07/18
JO - Genetics
DO - 10.1093/genetics/iyag188
UR - https://doi.org/10.1093/genetics/iyag188
AB - Neuropeptides modulate brain function by acting as ligands for a wide range of receptors. Systematic pharmacological screening efforts revealed extensive promiscuity in peptide-receptor pairs. However, the endogenous receptors and functions of promiscuous neuropeptides remain poorly understood. Here, we investigated how the Caenorhabditis elegans promiscuous RFamide-peptide FLP-14 and its receptors modulate a circuit for O2-evoked locomotory arousal. We show that FLP-14 peptides released from O2-sensing neurons and interneurons attenuate O2-evoked arousal by acting on 3 phylogenetically diverse G protein-coupled receptors (DMSR-3, FRPR-8, and NPR-40). Loss of each receptor individually confers strong hyperarousal by O2 comparable to the loss of flp-14. Distinct FLP-14 receptors have nonredundant roles in different target cells, including RID and RIM interneurons, that correlate antagonistically with locomotory arousal. Our results show that FLP-14 signaling requires coordinated modulation of multiple circuit nodes through distinct receptors in attenuating O2-evoked arousal. This promiscuous RFamide peptide network is reminiscent of monoaminergic neuromodulatory networks, which shape behavior through multiple receptors that differentially regulate distributed target neurons.
SN - 0016-6731
SN - 1943-2631
ER -