Adipokinetic hormone signaling through the gonadotropin-releasing hormone receptor modulates egg-laying in Caenorhabditis elegans

Abstract

In mammals, hypothalamic gonadotropin-releasing hormone (GnRH) is a neuropeptide that stimulates the release of gonadotropins from the anterior pituitary. The existence of a putative functional equivalent of this reproduction axis in protostomian invertebrates has been a matter of debate. In this study, the ligand for the GnRH receptor in the nematode Caenorhabditis elegans (Ce-GnRHR) was found using a bioinformatics approach. The peptide and its precursor are reminiscent of both insect adipokinetic hormones and GnRH-preprohormone precursors from tunicates and higher vertebrates. We cloned the AKH-GnRH-like preprohormone and the Ce-GnRHR and expressed the GPCR in HEK293T cells. The GnRHR was activated by the C. elegans AKH-GnRH-like peptide (EC50 ‫؍‬ 150 nM) and by Drosophila AKH and other nematode AKH-GnRHs that we found in EST databases. Analogous to both insect AKH receptor and vertebrate GnRH receptor signaling, Ce-AKH-GnRH activated its receptor through a G␣q protein with Ca 2؉ as a second messenger. Gene silencing of Ce-GnRHR, Ce-AKHGnRH, or both resulted in a delay in the egg-laying process, comparable to a delay in puberty in mammals lacking a normal dose of GnRH peptide or with a mutated GnRH precursor or receptor gene. The present data support the view that the AKH-GnRH signaling system probably arose very early in metazoan evolution and that its role in reproduction might have been developed before the divergence of protostomians and deuterostomians.C. elegans ͉ G protein-coupled receptor ͉ molecular evolution ͉ neuropeptide ͉ neuroendocrinology

Global view of the evolution and diversity of metazoan neuropeptide signaling

“…These pNPs in turn connect to the ancestral bilaterian gonadotropin-releasing hormone (GnRH)/corazonin family, suggesting a complex scenario of duplication and gene loss for the origin of these families from repetitive Wamides (38). A relationship between GnRH and AKH has been proposed based on shared sequence features (38) and the relatedness of the receptors (39,40). The clustering of GnRH/ AKH receptors in the GPCR map confirms this (Fig.…”

Identification and Functional Characterization of Two Orphan G-protein-coupled Receptors for Adipokinetic Hormones from Silkworm Bombyx mori

“…AKHs are initially known to mobilize carbohydrates and lipids during energy-expensive activities like long distance flight. Recent studies have highlighted the critical role of AKH in modulating fundamental physiological processes, such as sugar homeostasis, lipid metabolism, and reproduction (6,7). The structure of AKH was first identified from the locusts Locusta migratoria and Schistocerca gregaria (8).…”

The Adipokinetic Hormone Receptor Modulates Sexual Behavior, Pheromone Perception and Pheromone Production in a Sex-Specific and Starvation-Dependent Manner in Drosophila melanogaster

“…This hormone acts via a specific receptor and is thought to synchronize reproduction with energetically favorable conditions (Kauffman and Rissman, 2004). In invertebrates, the adipokinetic hormone receptor (AKHR) is structurally and evolutionarily related to the mammalian GnRH receptor (Lindemans et al, 2009). AKHR is activated by adipokinetic hormone (AKH), which is, however, homologous to glucagon instead of GnRH.…”

“…Recently, Lindemans et al (2009) demonstrated that AKH signaling through the GnRH receptor modulates egg-laying behavior in the nematode Caenorhabditis elegans. They therefore hypothesized that the role of the AKH/GnRH pathway on reproduction might have been developed before the divergence of protostomians and deuterostomians.…”