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Urbilaterian origin of paralogous GnRH and corazonin neuropeptide signalling pathways.

ABSTRACT: Gonadotropin-releasing hormone (GnRH) is a key regulator of reproductive maturation in humans and other vertebrates. Homologs of GnRH and its cognate receptor have been identified in invertebrates-for example, the adipokinetic hormone (AKH) and corazonin (CRZ) neuropeptide pathways in arthropods. However, the precise evolutionary relationships and origins of these signalling systems remain unknown. Here we have addressed this issue with the first identification of both GnRH-type and CRZ-type signalling systems in a deuterostome-the echinoderm (starfish) Asterias rubens. We have identified a GnRH-like neuropeptide (pQIHYKNPGWGPG-NH2) that specifically activates an A. rubens GnRH-type receptor and a novel neuropeptide (HNTFTMGGQNRWKAG-NH2) that specifically activates an A. rubens CRZ-type receptor. With the discovery of these ligand-receptor pairs, we demonstrate that the vertebrate/deuterostomian GnRH-type and the protostomian AKH systems are orthologous and the origin of a paralogous CRZ-type signalling system can be traced to the common ancestor of the Bilateria (Urbilateria).

SUBMITTER: Tian S

PROVIDER: S-EPMC4923880 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Urbilaterian origin of paralogous GnRH and corazonin neuropeptide signalling pathways.

Tian Shi S Zandawala Meet M Beets Isabel I Baytemur Esra E Slade Susan E SE Scrivens James H JH Elphick Maurice R MR

Scientific reports 20160628

Gonadotropin-releasing hormone (GnRH) is a key regulator of reproductive maturation in humans and other vertebrates. Homologs of GnRH and its cognate receptor have been identified in invertebrates-for example, the adipokinetic hormone (AKH) and corazonin (CRZ) neuropeptide pathways in arthropods. However, the precise evolutionary relationships and origins of these signalling systems remain unknown. Here we have addressed this issue with the first identification of both GnRH-type and CRZ-type sig ...[more]

PMID: 27350121

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Project description:Homologs of the vertebrate neuropeptide gonadotropin-releasing hormone (GnRH) have been identified in invertebrates, including the insect neuropeptide corazonin (CRZ). Recently, we reported the discovery of GnRH-type and CRZ-type signaling systems in an echinoderm, the starfish Asterias rubens, demonstrating that the evolutionary origin of paralogous GnRH-type and CRZ-type neuropeptides can be traced back to the common ancestor of protostomes and deuterostomes. Here, we have investigated the physiological roles of the GnRH-type (ArGnRH) and the CRZ-type (ArCRZ) neuropeptides in A. rubens, using mRNA in situ hybridization, immunohistochemistry and in vitro pharmacology. ArGnRH precursor (ArGnRHP)-expressing cells and ArGnRH-immunoreactive cells and/or processes are present in the radial nerve cords, circumoral nerve ring, digestive system (e.g., cardiac stomach and pyloric stomach), body wall-associated muscle (apical muscle), and appendages (tube feet, terminal tentacle). The general distribution of ArCRZ precursor (ArCRZP)-expressing cells is similar to that of ArGnRHP, but with specific local differences. For example, cells expressing ArGnRHP are present in both the ectoneural and hyponeural regions of the radial nerve cords and circumoral nerve ring, whereas cells expressing ArCRZP were only observed in the ectoneural region. In vitro pharmacological experiments revealed that both ArGnRH and ArCRZ cause contraction of cardiac stomach, apical muscle, and tube foot preparations. However, ArGnRH was more potent/effective than ArCRZ as a contractant of the cardiac stomach, whereas ArCRZ was more potent/effective than ArGnRH as a contractant of the apical muscle. These findings demonstrate that both ArGnRH and ArCRZ are myoexcitatory neuropeptides in starfish, but differences in their expression patterns and pharmacological activities are indicative of distinct physiological roles. This is the first study to investigate the physiological roles of both GnRH-type and CRZ-type neuropeptides in a deuterostome, providing new insights into the evolution and comparative physiology of these paralogous neuropeptide signaling systems in the Bilateria.

Project description:Commercial gonadotropin-releasing hormone (GnRH) antagonists differ by 1-2 amino acids and are used to inhibit gonadotropin production during assisted reproduction technologies (ART). In this study, potencies of three GnRH antagonists, Cetrorelix, Ganirelix and Teverelix, in inhibiting GnRH-mediated intracellular signaling, were compared in vitro. GnRH receptor (GnRHR)-transfected HEK293 and neuroblastoma-derived SH-SY5Y cell lines, as well as mouse pituitary LβT2 cells endogenously expressing the murine GnRHR, were treated with GnRH in the presence or absence of the antagonist. We evaluated intracellular calcium (Ca2+) and cAMP increases, cAMP-responsive element binding-protein (CREB) and extracellular-regulated kinase 1 and 2 (ERK1/2) phosphorylation, β-catenin activation and mouse luteinizing-hormone β-encoding gene (Lhb) transcription by bioluminescence resonance energy transfer (BRET), Western blotting, immunostaining and real-time PCR as appropriate. The kinetics of GnRH-induced Ca2+ rapid increase revealed dose-response accumulation with potency (EC50) of 23 nM in transfected HEK293 cells, transfected SH-SY5Y and LβT2 cells. Cetrorelix inhibited the 3 × EC50 GnRH-activated calcium signaling at concentrations of 1 nM-1 µM, demonstrating higher potency than Ganirelix and Teverelix, whose inhibitory doses fell within the 100 nM-1 µM range in both transfected HEK293 and SH-SY5Y cells in vitro. In transfected SH-SY5Y, Cetrorelix was also significantly more potent than other antagonists in reducing GnRH-mediated cAMP accumulation. All antagonists inhibited pERK1/2 and pCREB activation at similar doses, in LβT2 and transfected HEK293 cells treated with 100 nM GnRH. Although immunostainings suggested that Teverelix could be less effective than Cetrorelix and Ganirelix in inhibiting 1 µM GnRH-induced β-catenin activation, Lhb gene expression increase occurring upon LβT2 cell treatment by 1 µM GnRH was similarly inhibited by all antagonists. To conclude, this study has demonstrated Cetrorelix-, Ganirelix- and Teverelix-specific biased effects at the intracellular level, not affecting the efficacy of antagonists in inhibiting Lhb gene transcription.

Project description:Neuropeptides and their G protein-coupled receptors (GPCRs) play a central role in the physiology of insects. One large family of insect neuropeptides are the adipokinetic hormones (AKHs), which mobilize lipids and carbohydrates from the insect fat body. Other peptides are the corazonins that are structurally related to the AKHs but represent a different neuropeptide signaling system. We have previously cloned an orphan GPCR from the malaria mosquito Anopheles gambiae that was structurally intermediate between the A. gambiae AKH and corazonin GPCRs. Using functional expression of the receptor in cells in cell culture, we have now identified the ligand for this orphan receptor as being pQVTFSRDWNAamide, a neuropeptide that is structurally intermediate between AKH and corazonin and that we therefore named ACP (AKH/corazonin-related peptide). ACP does not activate the A. gambiae AKH and corazonin receptors and, vice versa, AKH and corazonin do not activate the ACP receptor, showing that the ACP/receptor couple is an independent and so far unknown peptidergic signaling system. Because ACP is structurally intermediate between AKH and corazonin and the ACP receptor between the AKH and corazonin receptors, this is a prominent example of receptor/ligand co-evolution, probably originating from receptor and ligand gene duplications followed by mutations and evolutionary selection, thereby yielding three independent hormonal systems. The ACP signaling system occurs in the mosquitoes A. gambiae, Aedes aegypti, and Culex pipiens (Diptera), the silkworm Bombyx mori (Lepidoptera), the red flour beetle Tribolium castaneum (Coleoptera), the parasitic wasp Nasonia vitripennis (Hymenoptera), and the bug Rhodnius prolixus (Hemiptera). However, the ACP system is not present in 12 Drosophila species (Diptera), the honeybee Apis mellifera (Hymenoptera), the pea aphid Acyrthosiphon pisum (Hemiptera), the body louse Pediculus humanus (Phthiraptera), and the crustacean Daphnia pulex, indicating that it has been lost several times during arthropod evolution. In particular, this frequent loss of hormonal systems is unique for arthropods compared with vertebrates.

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Urbilaterian origin of paralogous GnRH and corazonin neuropeptide signalling pathways.

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Urbilaterian origin of paralogous GnRH and corazonin neuropeptide signalling pathways.

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