The neuropeptide FLP-11 induces and self-inhibits sleep through the receptor DMSR-1 in Caenorhabiditis elegans

Lorenzo Rossi; Kenneth Amoako; Inka Busack; Luca Golinelli; Amy Courtney; Judith Besseling; William Schafer; Isabel Beets; Henrik Bringmann

doi:10.1016/j.cub.2025.03.039

The neuropeptide FLP-11 induces and self-inhibits sleep through the receptor DMSR-1 in Caenorhabiditis elegans

Curr Biol. 2025 May 5;35(9):2183-2194.e10. doi: 10.1016/j.cub.2025.03.039. Epub 2025 Apr 23.

Authors

Lorenzo Rossi¹, Kenneth Amoako¹, Inka Busack¹, Luca Golinelli², Amy Courtney³, Judith Besseling⁴, William Schafer⁵, Isabel Beets², Henrik Bringmann⁶

Affiliations

¹ Biotechnology Center, Center for Molecular and Cellular Bioengineering, Technische Universität Dresden, Am Tatzberg 47/49, 01307 Dresden, Germany.
² Department of Biology, KU Leuven, Naamsestraat 59, 3000 Leuven, Belgium.
³ MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK.
⁴ Max Planck Institute of Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany.
⁵ Department of Biology, KU Leuven, Naamsestraat 59, 3000 Leuven, Belgium; MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK.
⁶ Biotechnology Center, Center for Molecular and Cellular Bioengineering, Technische Universität Dresden, Am Tatzberg 47/49, 01307 Dresden, Germany; Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Fetscherstraße 74, 01307 Dresden, Germany. Electronic address: henrik.bringmann@tu-dresden.de.

PMID: 40273913
DOI: 10.1016/j.cub.2025.03.039

Abstract

Sleep is caused by the depolarization of sleep-active neurons, which secrete gamma-aminobutyric acid (GABA) and neuropeptides such as conserved RFamide (c-terminal Arg-Phe-NH₂ motif) neuropeptides to dictate when an organism falls asleep and when it wakes up.¹^,²^,³^,⁴^,⁵^,⁶^,⁷^,⁸^,⁹^,¹⁰ However, the mechanisms by which neurotransmission from sleep-active neurons induces sleep and determines the duration of sleep remain poorly understood. Sleep in Caenorhabditis elegans crucially requires the single sleep-active RIS neuron, which induces sleep via the release of FLP-11 RFamide neuropeptides.⁸^,¹¹ However, how RIS and FLP-11 control sleep is not well understood, as the receptor through which FLP-11 acts has yet to be identified. In this study, we discovered that RIS and FLP-11 control sleep through the G_i/o-protein coupled receptor DroMyoSuppressin receptor related 1 (DMSR-1).¹²^,¹³ Using cell-specific knockdowns,¹⁴ we demonstrate that dmsr-1 induces sleep by acting in cholinergic neurons downstream of RIS activation. Pharmacological intervention indicates that inhibiting cholinergic signaling is necessary for sleep. Consistently, DMSR-1 expression in cholinergic neurons is essential for core sleep functions, including protective gene expression and survival. In contrast, we found that dmsr-1 in RIS mediates negative feedback control during sleep that limits RIS calcium activation and the duration of sleep. Consequently, dmsr-1 in RIS inhibits protective gene expression and survival. Thus, DMSR-1 controls both the initiation and limitation of sleep, effectively coupling sleep induction with a sleep-stop signal. RFamide neuropeptide-GPCR signaling might underlie similar dual mechanisms of sleep control in other species, and self-inhibition of sleep-active neurons might represent a conserved mechanism for limiting the duration of sleep. VIDEO ABSTRACT.

Keywords: C. elegans; DMSR-1; FLP-11; GPCR; Gi/o; RFamide; calcium imaging; homeostasis; optogenetics; sleep.

MeSH terms

Animals
Caenorhabditis elegans Proteins* / genetics
Caenorhabditis elegans Proteins* / metabolism
Caenorhabditis elegans* / genetics
Caenorhabditis elegans* / physiology
Neurons / metabolism
Neurons / physiology
Neuropeptides* / genetics
Neuropeptides* / metabolism
Receptors, G-Protein-Coupled* / genetics
Receptors, G-Protein-Coupled* / metabolism
Sleep* / physiology

Substances

Neuropeptides
Caenorhabditis elegans Proteins
Receptors, G-Protein-Coupled