Peptidergic Signaling Systems Research Articles

Discovery of Human Signaling Systems: Pairing Peptides to G Protein-Coupled Receptors

SummaryThe peptidergic system is the most abundant network of ligand-receptor-mediated signaling in humans. However, the physiological roles remain elusive for numerous peptides and more than 100 G protein-coupled receptors (GPCRs). Here we report the pairing of cognate peptides and receptors. Integrating comparative genomics across 313 species and bioinformatics on all protein sequences and structures of human class A GPCRs, we identify universal characteristics that uncover additional potential peptidergic signaling systems. Using three orthogonal biochemical assays, we pair 17 proposed endogenous ligands with five orphan GPCRs that are associated with diseases, including genetic, neoplastic, nervous and reproductive system disorders. We also identify additional peptides for nine receptors with recognized ligands and pathophysiological roles. This integrated computational and multifaceted experimental approach expands the peptide-GPCR network and opens the way for studies to elucidate the roles of these signaling systems in human physiology and disease.Video

Identification of peptide hormones and their cognate receptors in Jasus edwardsii – A potential resource for the development of new aquaculture management strategies for rock/spiny lobsters

The southern rock lobster, Jasus edwardsii, is a member of the Achelata native to New Zealand and southern Australia that in addition to being the subject of an extensive wild fishery, has been proposed as a target for aquaculture. One obstacle to the farming of this species is its long maturation period, and the development of large-scale commercial aquaculture will require management strategies that reduce the duration of its time in culture. Increasing food intake can result in increased growth rates, and may be one way to reduce the time to market for farmed lobsters. In crustaceans, food intake and growth are regulated by locally released and/or circulating paracrines/hormones, the largest class being peptides. In the study presented here, the native peptides of J. edwardsii, as well as their cognate receptors, were predicted using a publicly accessible transcriptome. Two hundred and seventy distinct peptides were identified (the largest peptidome currently extant for any decapod), 122 of which possess structures that place them into generally recognized arthropod peptide families, i.e., adipokinetic hormone-corazonin-like peptide, allatostatin A, allatostatin B, allatostatin C, bursicon, CCHamide, corazonin, crustacean cardioactive peptide, crustacean hyperglycemic hormone/molt-inhibiting hormone, diuretic hormone 31, diuretic hormone 44, eclosion hormone, elevenin, FMRFamide-like peptide, glycoprotein hormone, GSEFLamide, inotocin, insulin-like peptide, leucokinin, myosuppressin, neuroparsin, neuropeptide F, orcokinin, orcomyotropin, pigment dispersing hormone, proctolin, pyrokinin, red pigment concentrating hormone, RYamide, short neuropeptide F, SIFamide, sulfakinin, tachykinin-related peptide and trissin. Putative receptors for many of the identified peptide groups were also identified via transcriptome mining. This is the first report of a peptidome and peptide receptors for J. edwardsii, and as such, provides a powerful new resource for beginning to investigate the physiological/behavioral roles played by peptidergic signaling systems in this species, including the roles they play in controlling processes that are of importance for improving aquaculture management strategies.

Amyloid beta peptides, locus coeruleus-norepinephrine system and dense core vesicles

The evolution of peptidergic signaling systems in the central nervous system serves a distinct and crucial role in brain processes and function. The diversity of physiological peptides and the complexity of their regulation and secretion from the dense core vesicles (DCV) throughout the brain is a topic greatly in need of investigation, though recent years have shed light on cellular and molecular mechanisms that are summarized in this review. Here, we focus on the convergence of peptidergic systems onto the Locus Coeruleus (LC), the sole provider of norepinephrine (NE) to the cortex and hippocampus, via large DCV. As the LC-NE system is one of the first regions of the brain to undergo degeneration in Alzheimer’s Disease (AD), and markers of DCV have consistently been demonstrated to have biomarker potential for AD progression, here we summarize the current literature linking the LC-NE system with DCV dysregulation and Aβ peptides. We also include neuroanatomical data suggesting that the building blocks of senile plaques, Aβ monomers, may be localized to DCV of the LC and noradrenergic axon terminals of the prefrontal cortex. Finally, we explore the putative consequences of chronic stress on Aβ production and the role that DCV may play in LC degeneration. Clinical data of immunological markers of DCV in AD patients are discussed.

Peptidergic signaling in the tadpole shrimp Triops newberryi: A potential model for investigating the roles played by peptide paracrines/hormones in adaptation to environmental change

Peptides are the largest/most diverse class of molecules used by animals for chemical communication, and with their cognate receptors, are key players in modulating physiological/behavioral control systems, including those involved in adaptation to environmental change. Crustaceans have long served as models for investigating peptidergic control of physiology/behavior, and members of Notostraca, an ancient branchiopod order, have recently been proposed as models for investigating the genetic/physiological underpinnings of ecoresponsiveness; nothing is currently known about the genes/proteins underlying peptidergic signaling in any member of this crustacean taxon. Transcriptome mining is a powerful tool for peptidome prediction in crustaceans, and all large-scale discovery of crustacean peptide receptors has been achieved via transcriptomics. Here, in silico transcriptome mining was used to elucidate the peptidergic signaling systems of the tadpole shrimp Triops newberryi, a member of Notostraca. Transcripts encoding putative precursor proteins and/or receptors for 28 peptide families were identified within the T. newberryi dataset. The deduced precursor proteins included those for allatostatin A, allatostatin B, allatostatin C, allatotropin, bursicon, CCHamide, crustacean cardioactive peptide, crustacean hyperglycemic hormone, diuretic hormone 44, ecdysis-triggering hormone, eclosion hormone, elevenin, FMRFamide-like peptide, glycoprotein hormone, GSEFLamide, inotocin, insulin-like peptide, neuroparsin, neuropeptide F, orcokinin/orcomyotropin, proctolin, pyrokinin/periviscerokinin, SIFamide, sulfakinin and tachykinin-related peptide; 117 distinct mature peptides were predicted from the collective set of deduced pre/preprohormones. Transcripts encoding putative receptors for most of the abovementioned peptide groups were also identified from the T. newberryi assembly, as were those for several families for which no precursors were found, i.e., corazonin, RYamide and short neuropeptide F. This is the first description of a peptidome and peptide receptors from any member of the Notostraca, and as such, provide a foundation for beginning to investigate the roles played by peptidergic signaling systems in T. newberryi and other notostracans, including how they may contribute to modulating organism-environment interactions.

Identification of the first neuropeptides from the Amphipoda (Arthropoda, Crustacea)

Despite being used as models in the field of ecotoxicology, including use in studies of endocrine disruption, little is known about the hormonal systems of amphipods, particularly their peptidergic signaling systems. Here, transcriptome shotgun assembly (TSA) sequences were used to predict the structures of the first neuropeptides from members of this crustacean order. Using a well-established workflow, BLAST searches of the extant amphipod TSA data were conducted for putative peptide-encoding transcripts. The pre/preprohormones deduced from the identified TSA sequences were then used to predict the mature structures of amphipod neuropeptides. In total, 43 putative peptide-encoding transcripts were identified from three amphipods, Echinogammarus veneris, Hyalella azteca and Melita plumulosa. Collectively, 139 distinct mature peptides (110 from E. veneris alone) were predicted from these TSA sequences. The identified peptides included members of the adipokinetic hormone/red pigment concentrating hormone, allatostatin A, allatostatin B, allatostatin C, bursicon α, bursicon β, crustacean hyperglycemic hormone, diuretic hormone 31, FLRFamide, molt-inhibiting hormone, myosuppressin, neuroparsin, neuropeptide F, orcokinin, pigment dispersing hormone (PDH), proctolin, RYamide, SIFamide, sulfakinin and tachykinin-related peptide families. Of particular note were the identifications of orcokinins possessing SFDEIDR– rather than the typical NFDEIDR– amino-termini, e.g. SFDEINRSNFGFN, a carboxyl-terminally amidated orcokinin, i.e. SFDEINRSNFGFSamide, PDHs longer than the stereotypical 18 amino acids, e.g. NSELLNTLLGSKSLAALRAAamide, and a 13 rather than 12 amino acid long SIFamide, i.e. GPYRKPPFNGSIFamide. These data not only provide the first descriptions of native amphipod neuropeptides, but also represent a new resource for initiating investigations of peptidergic signaling in the Amphipoda.

Identification and developmental expression of the enzymes responsible for dopamine, histamine, octopamine and serotonin biosynthesis in the copepod crustacean Calanus finmarchicus

Neurochemicals are likely to play key roles in physiological/behavioral control in the copepod crustacean Calanus finmarchicus, the biomass dominant zooplankton for much of the North Atlantic Ocean. Previously, a de novo assembled transcriptome consisting of 206,041 unique sequences was used to characterize the peptidergic signaling systems of Calanus. Here, this assembly was mined for transcripts encoding enzymes involved in amine biosynthesis. Using known Drosophila melanogaster proteins as templates, transcripts encoding putative Calanus homologs of tryptophan-phenylalanine hydroxylase (dopamine, octopamine and serotonin biosynthesis), tyrosine hydroxylase (dopamine biosynthesis), DOPA decarboxylase (dopamine and serotonin biosynthesis), histidine decarboxylase (histamine biosynthesis), tyrosine decarboxylase (octopamine biosynthesis), tyramine β-hydroxylase (octopamine biosynthesis) and tryptophan hydroxylase (serotonin biosynthesis) were identified. Reverse BLAST and domain analyses show that the proteins deduced from these transcripts possess sequence homology to and the structural hallmarks of their respective enzyme families. Developmental profiling revealed a remarkably consistent pattern of expression for all transcripts, with the highest levels of expression typically seen in the early nauplius and early copepodite. These expression patterns suggest roles for amines during development, particularly in the metamorphic transitions from embryo to nauplius and from nauplius to copepodite. Taken collectively, the data presented here lay a strong foundation for future gene-based studies of aminergic signaling in this and other copepod species, in particular assessment of the roles they may play in developmental control.

Molecular evolution of peptidergic signaling systems in bilaterians.

Peptide hormones and their receptors are widespread in metazoans, but the knowledge we have of their evolutionary relationships remains unclear. Recently, accumulating genome sequences from many different species have offered the opportunity to reassess the relationships between protostomian and deuterostomian peptidergic systems (PSs). Here we used sequences of all human rhodopsin and secretin-type G protein-coupled receptors as bait to retrieve potential homologs in the genomes of 15 bilaterian species, including nonchordate deuterostomian and lophotrochozoan species. Our phylogenetic analysis of these receptors revealed 29 well-supported subtrees containing mixed sets of protostomian and deuterostomian sequences. This indicated that many vertebrate and arthropod PSs that were previously thought to be phyla specific are in fact of bilaterian origin. By screening sequence databases for potential peptides, we then reconstructed entire bilaterian peptide families and showed that protostomian and deuterostomian peptides that are ligands of orthologous receptors displayed some similarity at the level of their primary sequence, suggesting an ancient coevolution between peptide and receptor genes. In addition to shedding light on the function of human G protein-coupled receptor PSs, this work presents orthology markers to study ancestral neuron types that were probably present in the last common bilaterian ancestor.

Peptidergic signaling in Calanus finmarchicus (Crustacea, Copepoda): In silico identification of putative peptide hormones and their receptors using a de novo assembled transcriptome

The copepod Calanus finmarchicus is the most abundant zooplankton species in the North Atlantic. While the life history of this crustacean is well studied, little is known about its peptidergic signaling systems despite the fact that these pathways are undoubtedly important components of its physiological/behavioral control systems. Here we have generated and used a de novo assembled transcriptome for C. finmarchicus (206,041 sequences in total) to identify peptide precursor proteins and receptors. Using known protein queries, 34 transcripts encoding peptide preprohormones and 18 encoding peptide receptors were identified. Using a combination of online software programs and homology to known arthropod isoforms, 148 mature peptides were predicted from the deduced precursors, including members of the allatostatin-A, allatostatin-B, allatostatin-C, bursicon, crustacean cardioactive peptide (CCAP), crustacean hyperglycemic hormone, diuretic hormone 31 (DH31), diuretic hormone 44 (DH44), FMRFamide-like peptide (myosuppressin, neuropeptide F [NPF] and extended FL/IRFamide subfamilies), leucokinin, neuroparsin, orcokinin, orcomyotropin, periviscerokinin, RYamide and tachykinin-related peptide (TRP) families. The identified receptors included ones for allatostatin-A, allatostatin-C, bursicon, CCAP, DH31, DH44, ecdysis-triggering hormone, NPF, short NPF, FMRFamide, insulin-like peptide, leucokinin, periviscerokinin, pigment dispersing hormone, and TRP. Developmental profiling of the identified transcripts in embryos, early nauplii, late nauplii, early copepodites, late copepodites, and adult females was also undertaken, with all showing the highest expression levels in the naupliar and copepodite stages. Collectively, these data radically expand the catalog of known C. finmarchicus peptidergic signaling proteins and provide a foundation for experiments directed at understanding the physiological roles served by them in this species.