Adipokinetic hormones and their G protein-coupled receptors emerged in Lophotrochozoa.

Li S ，Hauser F ，Skadborg SK ，Nielsen SV ，Kirketerp-Møller N ，Grimmelikhuijzen CJ ... -  《Scientific Reports》

Evolution of the AKH/corazonin/ACP/GnRH receptor superfamily and their ligands in the Protostomia.

In this review we trace the evolutionary connections between GnRH receptors from vertebrates and the receptors for adipokinetic hormone (AKH), AKH/corazonin-related peptide (ACP), and corazonin from arthropods. We conclude that these G protein-coupled receptors (GPCRs) are closely related and have a common evolutionary origin, which dates back to the split of Proto- and Deuterostomia, about 700 million years ago. We propose that in the protostomian lineage, the ancestral GnRH-like receptor gene duplicated as did its GnRH-like ligand gene, followed by diversification, leading to (i) a corazonin receptor gene and a corazonin-like ligand gene, and (ii) an AKH receptor gene and an AKH-like ligand gene in the Mollusca and Annelida. Subsequently, the AKH receptor and ligand genes duplicated once more, yielding the situation that we know from arthropods today, where three independent hormonal systems exist, signalling with AKH, ACP, and corazonin. Our model for the evolution of GnRH signaling in the Protostomia is a striking example of receptor-ligand co-evolution. This model has been developed using several bioinformatics tools (TBLASTN searches, phylogenetic tree analyses), which also helped us to annotate six novel AKH preprohormones and their corresponding AKH sequences from the following molluscs: the sea hare Aplysia californica (AKH sequence: pQIHFSPDWGTamide), the sea slug Tritonia diomedea (pQIHFSPGWEPamide), the fresh water snail Bithynia siamensis goniomphalos (pQIHFTPGWGSamide), the owl limpet Lottia gigantea (pQIHFSPTWGSamide), the oyster Crassostrea gigas (pQVSFSTNWGSamide), and the freshwater pearl mussel Hyriopsis cumingii (pQISFSTNWGSamide). We also found AKHs in the tardigrade Hysibius dujardini (pQLSFTGWGHamide), the rotifer Brachionus calycifloros (pQLTFSSDWSGamide), and the penis worm Priapulus caudatus (pQIFFSKGWRGamide). This is the first report, showing that AKH signaling is widespread in molluscs.

Hauser F ，Grimmelikhuijzen CJ 《-》

Discovery of a novel insect neuropeptide signaling system closely related to the insect adipokinetic hormone and corazonin hormonal systems.

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.

Hansen KK ，Stafflinger E ，Schneider M ，Hauser F ，Cazzamali G ，Williamson M ，Kollmann M ，Schachtner J ，Grimmelikhuijzen CJ ... -  《-》

The tick Ixodes scapularis has five different GPCRs specifically activated by ACP (adipokinetic hormone/corazonin-related peptide).

Insects have about 50 neuropeptide genes and about 70 genes, coding for neuropeptide G protein-coupled receptors (GPCRs). An important, but small family of evolutionarily related insect neuropeptides consists of adipokinetic hormone (AKH), corazonin, and AKH/corazonin-related peptide (ACP). Normally, insects have one specific GPCR for each of these neuropeptides. The tick Ixodes scapularis is not an insect, but belongs to the subphylum Chelicerata, which comprises ticks, scorpions, mites, spiders, and horseshoe crabs. Many of the neuropeptides and neuropeptide GPCRs occurring in insects, also occur in chelicerates, illustrating that insects and chelicerates are evolutionarily closely related. The tick I. scapularis is an ectoparasite and health risk for humans, because it infects its human host with dangerous pathogens during a blood meal. Understanding the biology of ticks will help researchers to prevent tick-borne diseases. By annotating the I. scapularis genome sequence, we previously found that ticks contain as many as five genes, coding for presumed ACP receptors. In the current paper, we cloned these receptors and expressed each of them in Chinese Hamster Ovary (CHO) cells. Each expressed receptor was activated by nanomolar concentrations of ACP, demonstrating that all five receptors were functional ACP receptors. Phylogenetic tree analyses showed that the cloned tick ACP receptors were mostly related to insect ACP receptors and, next, to insect AKH receptors, suggesting that ACP receptor genes and AKH receptor genes originated by gene duplications from a common ancestor. Similar duplications have probably occurred for the ligand genes, during a process of ligand/receptor co-evolution. Interestingly, chelicerates, in contrast to all other arthropods, do not have AKH or AKH receptor genes. Therefore, the ancestor of chelicerates might have lost AKH and AKH receptor genes and functionally replaced them by ACP and ACP receptor genes. For the small family of AKH, ACP, and corazonin receptors and their ligands, gene losses and gene gains occur frequently between the various ecdysozoan clades. Tardigrades, for example, which are well known for their survival in extreme environments, have as many as ten corazonin receptor genes and six corazonin peptide genes, while insects only have one of each, or none.

Hauser F ，Stebegg M ，Al-Ribaty T ，Petersen LB ，Møller M ，Drag MH ，Sigurdsson HH ，Vilhelm MJ ，Thygesen G ，Grimmelikhuijzen CJP ... -  《-》

Mini-review: the evolution of neuropeptide signaling.

Neuropeptides and their G protein-coupled receptors (GPCRs) have an early evolutionary origin and are already abundant in basal animals with primitive nervous systems such as cnidarians (Hydra, jellyfishes, corals, and sea anemones). Most animals emerging after the Cnidaria belong to two evolutionary lineages, the Protostomia (to which the majority of invertebrates belong) and Deuterostomia (to which some minor groups of invertebrates, and all vertebrates belong). These two lineages split about 700 million years (Myr) ago. Many mammalian neuropeptide GPCRs have orthologues in the Protostomia and this is also true for some of the mammalian neuropeptides. Examples are oxytocin/vasopressin, GnRH, gastrin/CCK, and neuropeptide Y and their GPCRs. These results implicate that protostomes (for example insects and nematodes) can be used as models to study the biology of neuropeptide signaling.

Grimmelikhuijzen CJ ，Hauser F 《-》