RPamide neuropeptides NLP-22 and NLP-2 act through GnRH-like receptors to promote sleep and wakefulness in C. elegans

Abstract Sleep and wakefulness are fundamental behavioral states of which the underlying molecular principles are becoming slowly elucidated. Transitions between these states require the coordination of multiple neurochemical and modulatory systems. In Caenorhabditis elegans sleep occurs during a larval transition stage called lethargus and is induced by somnogenic neuropeptides. Here, we identify two opposing neuropeptide/receptor signaling pathways: NLP-22 promotes behavioral quiescence, whereas NLP-2 promotes movement during lethargus, by signaling through gonadotropin-releasing hormone (GnRH) related receptors. Both NLP-2 and NLP-22 belong to the RPamide neuropeptide family and share sequence similarities with neuropeptides of the bilaterian GnRH, adipokinetic hormone (AKH) and corazonin family. RPamide neuropeptides dose-dependently activate the GnRH/AKH-like receptors GNRR-3 and GNRR-6 in a cellular receptor activation assay. In addition, nlp-22-induced locomotion quiescence requires the receptor gnrr-6. By contrast, wakefulness induced by nlp-2 overexpression is diminished by deletion of either gnrr-3 or gnrr-6. nlp-2 is expressed in a pair of olfactory AWA neurons and cycles with larval periodicity, as reported for nlp-22, which is expressed in RIA. Our data suggest that the somnogenic NLP-22 neuropeptide signals through GNRR-6, and that both GNRR-3 and GNRR-6 are required for the wake-promoting action of NLP-2 neuropeptides.