Abstract
<jats:p> Sleep-like quiescence is an evolutionarily conserved state essential for physiological homeostasis; however, its dysregulation can lead to sleep disorders such as narcolepsy, which can be caused by abnormal neuropeptide signaling. In <jats:italic>Caenorhabditis elegans</jats:italic> , the G-protein-coupled receptor NPR-14 belongs to the orexin/allatotropin receptor family and has been proposed as a homolog of mammalian orexin receptors. Using <jats:italic>npr-14</jats:italic> loss-of-function ( <jats:italic>lf</jats:italic> ) mutants, we demonstrate that NPR-14 promotes arousal and inhibits sleep-like quiescence. <jats:italic>npr-14(lf)</jats:italic> mutants exhibit prolonged quiescence, reduced locomotion, impaired sensory responses, and metabolic defects including elevated fat accumulation and decreased feeding and egg-laying. NPR-14 is expressed in ASH and ASI sensory neurons and in GABAergic DD, VD, and VC motor neurons, positioning it to modulate both sensory-motor integration and motor output directly. Genetic epistasis analysis revealed that NPR-14 functions upstream of EGL-4/protein kinase G (PKG): <jats:italic>egl-4</jats:italic> loss-of-function suppressed the enhanced quiescence of <jats:italic>npr-14</jats:italic> mutants, while <jats:italic>egl-4</jats:italic> gain-of-function phenotypes were not enhanced by loss of <jats:italic>npr-14</jats:italic> . Caffeine treatment partially suppressed <jats:italic>npr-14</jats:italic> mutant quiescence, suggesting convergence with adenosine-sensitive arousal pathways. These findings establish NPR-14 as a wake-promoting GPCR that inhibits EGL-4/PKG signalling to regulate quiescence and arousal. The NPR-14EGL-4 axis suggests functional parallels to arousal regulation in other systems. </jats:p>