Sleep-like quiescence is an evolutionarily conserved behavioral state required for physiological homeostasis. Its dysregulation in higher organisms can lead to clinical disorders such as narcolepsy, which are linked to abnormal neuropeptide signalling. Studies in invertebrate models can reveal conserved molecular and circuit-level mechanisms that regulate transitions between arousal and quiescence. The present work characterizes a G-protein-coupled receptor, NPR-14, in Caenorhabditis elegans and defines its role in promoting wakefulness and inhibiting sleep-like quiescence.
NPR-14 is a G-protein-coupled receptor (GPCR) in C. elegans that belongs to the orexin/allatotropin receptor family. Based on sequence and family assignment, NPR-14 has been proposed as a homolog of mammalian orexin receptors, which are established regulators of arousal in vertebrates. The study frames NPR-14 within this conserved receptor family and tests its functional contribution to behavioural state regulation.
Loss-of-function (lf) mutants for npr-14 display a constellation of phenotypes consistent with reduced arousal and enhanced quiescence. Key reported features include prolonged sleep-like quiescence and reduced locomotion. In addition to behavioural slowing, sensory responses are impaired in npr-14(lf) animals, indicating that decreased arousal affects both spontaneous motor activity and stimulus-driven behaviours.
Metabolic and life-history traits are also altered in npr-14 mutants. The mutants exhibit elevated fat accumulation alongside decreased feeding and diminished egg-laying. These metabolic signs accompany the behavioural quiescence, consistent with a broad physiological shift associated with the mutant state.
NPR-14 expression was observed in both sensory and motor neurons, placing the receptor in positions to influence multiple nodes of sensorimotor control. Specifically, expression was reported in the ASH and ASI sensory neurons, which are involved in detecting environmental cues, and in GABAergic DD, VD, and VC motor neurons that contribute to motor output. This anatomical distribution supports a model in which NPR-14 modulates arousal by affecting sensory integration and direct motor pathways.
Epistasis experiments reported in the study indicate that NPR-14 functions upstream of EGL-4/protein kinase G (PKG) in the regulatory hierarchy controlling quiescence. The key findings are: loss-of-function of egl-4 suppressed the enhanced quiescence phenotype of npr-14 mutants, while gain-of-function phenotypes of egl-4 were not further enhanced by loss of npr-14. These genetic interactions place NPR-14 as an inhibitor of EGL-4/PKG signalling in the control of behavioural state, consistent with NPR-14 acting as a wake-promoting GPCR that restrains PKG-dependent promotion of quiescence.
The study tested pharmacological modulation and reports that caffeine treatment partially suppressed the quiescence phenotype of npr-14 mutants. Because caffeine is known to act on adenosine-sensitive arousal pathways, the partial rescue suggests that NPR-14-dependent arousal mechanisms converge with adenosine-sensitive signalling. The result indicates at least partial pharmacological overlap between NPR-14-mediated pathways and classical arousal-promoting neuromodulatory systems.
Taken together, the data establish NPR-14 as a wake-promoting GPCR in C. elegans that inhibits EGL-4/PKG signalling to regulate sleep-like quiescence and arousal. The receptor’s expression in sensory and motor neurons positions it to influence both sensory-motor integration and motor output directly. Genetic and pharmacological evidence indicates functional interactions with PKG-dependent pathways and partial convergence with adenosine-sensitive arousal mechanisms. The authors propose that the NPR-14–EGL-4 axis in C. elegans may reflect conserved features of arousal regulation across species.
Note: This study is a preprint posted on bioRxiv and has not been peer reviewed. Details beyond those reported in the article abstract, such as quantitative measures, experimental methods, or full dataset descriptions, were not reported in the provided source material.