-
[
Neuron,
2012]
Neuropeptides modulate neural circuits controlling adaptive animal behaviors and physiological processes, such as feeding/metabolism, reproductive behaviors, circadian rhythms, central pattern generation, and sensorimotor integration. Invertebrate model systems have enabled detailed experimental analysis using combined genetic, behavioral, and physiological approaches. Here we review selected examples of neuropeptide modulation in crustaceans, mollusks, insects, and nematodes, with a particular emphasis on the genetic model organisms Drosophila melanogaster and Caenorhabditis elegans, where remarkable progress has been made. On the basis of this survey, we provide several integrating conceptual principles for understanding how neuropeptides modulate circuit function, and also propose that continued progress in this area requires increased emphasis on the development of richer, more sophisticated behavioral paradigms.
-
[
J Physiol,
2014]
Dietary proteins are cleaved within the intestinal lumen to oligopeptides which are further processed to small peptides (di- and tripeptides) and free amino acids. Although the transport of amino acids is mediated by several specific amino acid transporters, the proton-coupled uptake of the more than 8000 different di- and tripeptides is performed by the high-capacity/low-affinity peptide transporter isoform PEPT1 (SLC15A1). Its wide substrate tolerance also allows the transport of a repertoire of structurally closely related compounds and drugs, which explains their high oral bioavailability and brings PEPT1 into focus for medical and pharmaceutical approaches. Although the first evidence for the interplay of nutrient supply and PEPT1 expression and function was described over 20 years ago, many aspects of the molecular processes controlling its transcription and translation and modifying its transporter properties are still awaiting discovery. The present review summarizes the recent knowledge on the factors modulating PEPT1 expression and function in Caenorhabditis elegans, Danio rerio, Mus musculus and Homo sapiens, with focus on dietary ingredients, transcription factors and functional modulators, such as the sodium-proton exchanger NHE3 and selected scaffold proteins.
-
[
Worm,
2013]
Neuropeptidergic signaling is widely adopted by animals for the regulation of physiology and behavior in a rapidly changing environment. The vasopressin/oxytocin neuropeptide family originates from an ancestral peptide precursor in the antecedent of protostomian and deuterostomian animals. In vertebrates, vasopressin and oxytocin have both hormonal effects on peripheral target tissues, such as in the regulation of reproduction and water balance, and neuromodulatory actions in the central nervous system controlling social behavior and cognition. The recent identification of vasopressin/oxytocin-related signaling in C. elegans reveals that this peptidergic system is widespread among nematodes. Genetic analysis of the C. elegans nematocin system denotes vasopressin/oxytocin-like peptides as ancient neuromodulators of neuronal circuits involved in reproductive behavior and associative learning, whereas former invertebrate studies focused on conserved peripheral actions of this peptide family. Nematocin provides neuromodulatory input into the gustatory plasticity circuit as well as into distinct male mating circuits to generate a coherent mating behavior. Molecular interactions are comparable to those underlying vasopressin- and oxytocin-mediated effects in the mammalian brain. Understanding how the vasopressin/oxytocin family fine-tunes neuronal circuits for social behavior, learning and memory poses a major challenge. Functional conservation of these effects in nematodes and most likely in other invertebrates enables the development of future models to help answering this question.
-
[
Peptides,
2015]
Forward or reverse movement in Caenorhabditis elegans is the result of sequential contraction of muscle cells arranged along the body. In larvae, muscle cells are innervated by distinct classes of motorneurons. B motorneurons regulate forward movement and A motorneurons regulate backward movement. Ablation of the D motor neurons results in animals that are uncoordinated in either direction, which suggests that D motorneurons regulate the interaction between the two circuits. C. elegans locomotion is dictated by inputs from interneurons that regulate the activity of motorneurons which coordinate muscle contraction to facilitate forward or backwards movement. As C. elegans moves through the environment, sensory neurons interpret chemical and mechanical information which is relayed to the motor neurons that control locomotory direction. A mechanosensory input known as light nose touch can be simulated in the laboratory by touching the nose of the animal with a human eyebrow hair. The recoil reaction that follows from light nose touch appears to be primarily mediated by glutamate release from the polymodal sensory neuron ASH. Numerous glutamate receptor types are found in different neurons and interneurons which suggest that several pathways may regulate the aversive response. Based on the phenotypes of mutants in which neuropeptide processing is abolished, neuropeptides play a role in circuit regulation. The light touch response is also regulated by transient receptor channel proteins and degenerin/epithelial sodium channels which modulate the activity of sensory neurons involved in the nose touch response.
-
[
Front Endocrinol (Lausanne),
2014]
In the three decades since the FMRFamide peptide was isolated from the mollusk Macrocallista nimbosa, structurally similar peptides sharing a C-terminal RFamide motif have been identified across the animal kingdom. FMRFamide-like peptides (FLPs) represent the largest known family of neuropeptides in invertebrates. In the phylum Nematoda, at least 32 flp-genes are classified, making the FLP system of nematodes unusually complex. The diversity of the nematode FLP complement is most extensively mapped in Caenorhabditis elegans, where over 70 FLPs have been predicted. FLPs have shown to be expressed in the majority of the 302 C. elegans neurons including interneurons, sensory neurons, and motor neurons. The vast expression of FLPs is reflected in the broad functional repertoire of nematode FLP signaling, including neuroendocrine and neuromodulatory effects on locomotory activity, reproduction, feeding, and behavior. In contrast to the many identified nematode FLPs, only few peptides have been assigned a receptor and there is the need to clarify the pathway components and working mechanisms of the FLP signaling network. Here, we review the diversity, distribution, and functions of FLPs in nematodes.
-
[
Parasitology,
1996]
The occurrence of classical neurotransmitter molecules and numerous peptidic messenger molecules in nematode nervous systems indicate that although structurally simple, nematode nervous systems are chemically complex. Thus far, studies oh one nematode neuropeptide family, namely the FMRFamide-related peptides (FaRPs), have revealed an unexpected variety of neuropeptide structures in both free-living and parasitic species. To date 23 nematode FaRPs have been structurally characterized including 12 from Ascaris suum, 8 from Caenorhabditis elegans, 5 from Panagrellus redivivus and 1 from Haemonchus contortus. Ten FaRP-encoding genes have been identified in Caenorhabditis elegans. However, the full complement of nematode neuronal messengers has yet to be described und unidentified nematode FaRPs await detection. Preliminary characterization of the actions of nematode neuropeptides on the somatic musculature and neurones of A. suum has revealed that these peptidic messengers have potent and complex effects. Identified complexities include the biphasic effects of KNEFIRFamide/KHEYLRFamide (AF1/2; relaxation of tone followed by oscillatory contractile activity) and KPNFIRFamide (PF4; rapid relaxation of tone followed by an increase in tone), the diverse actions of KSAYMRFamide (AF8 or PF3; relaxes dorsal muscles and contracts ventral muscles) and the apparent coupling of the relaxatory effects of SDPNFLRFamide/SADPNFLRFamide (PF1/PF2) to nitric oxide release. Indeed, all of the nematode FaRPs which have been tested on somatic muscle strips of A. suum have actions which are clearly physiologically distinguishable. Although we are a very long way from understanding how the actions of these peptides are coordinated, not only with those of each other but also with those of the classical transmitter molecules, to control nematode behaviour, their abundance coupled with their diversity of structure and function indicates a hitherto unidentified sophistication to nematode neuromuscular intergration.
-
[
Curr Opin Pharmacol,
2013]
A growing number of important human diseases are associated with the aggregation and deposition of incorrectly folded proteins in the form of highly structured amyloid fibrils. The aggregation process involves the formation of intermediate oligomeric assemblies with toxic properties. There are many commonalities among the different amyloid diseases, that is, similarities in structural features of amyloid fibrils or determinants of oligomer toxicity. Thus, a better knowledge of the general mechanisms of protein aggregation, the characterization of the aggregate's toxicity, and the identification of compounds interfering with these processes, may help for developing therapeutic strategies for different diseases. A variety of analytical methods are currently applied for these purposes. Here we focus on new applications of consolidated technologies which allow one to obtain informative data in a rapid and convenient manner. In particular, we discuss new applications of Surface Plasmon Resonance to study fibril elongation and to specifically recognize oligomers, as well as to screen for ligands of aggregated species and inhibitors of oligomer formation. We also review new advances in the use of wild-type or transgenic Caenorhabditis elegans as suitable in vivo models for the rapid and relatively inexpensive analysis of oligomer toxicity and for testing putative antagonists against this toxicity.
-
[
Trends Parasitol,
2009]
Neuropeptides are small messenger molecules that can be found in all metazoans, where they govern a diverse array of physiological processes. Because neuropeptides seem to be conserved among pest species, selected peptides can be considered as attractive targets for drug discovery. Much can be learned from the model system Caenorhabditis elegans because of the availability of a sequenced genome and state-of-the-art postgenomic technologies that enable characterization of endogenous peptides derived from neuropeptide-like protein (NLP) precursors. Here, we provide an overview of the NLP peptide family in C. elegans and discuss their resemblance with arthropod neuropeptides and their relevance for anthelmintic discovery.
-
[
Cell Mol Life Sci,
2000]
The cotransport of protons and peptides is now recognised as a major route by which dietary nitrogen is absorbed from the intestine, and filtered protein reabsorbed in the kidney. Recently, molecular biology has had a very substantial impact on the study of peptide transport, and here we review the molecular and functional information available within the framework of physiology. To this end we consider not only the mammalian peptide transporters and their tissue distribution and regulation but also those from other species (including Caenorhabditis elegans) which make up the proton-dependent oligopeptide transport superfamily. In addition, understanding the binding requirements for transported substrates may allow future design and targeted tissue delivery of peptide and peptidomimetic drugs. Finally, we aim to highlight some of the less well understood areas of peptide transport, in the hope that it will stimulate further research into this challenging yet exciting topic.
-
[
Traffic,
2009]
There is growing awareness that endocytic trafficking plays a critical role in cell-cell communication during animal development. We are beginning to understand how endocytosis can initiate, modulate or terminate signaling. In contrast, our knowledge of the mechanisms involved in secreting signaling peptides remains more limited, particularly when it comes to secretion at the apical surface in epithelial cells. In this study, we review the mechanisms that control secretion in Caenorhabditis elegans, focusing on the role of Patched family members and the V0 complex of the vacuolar-adenosine triphosphatase (V-ATPase) in secreting Hedgehog-related peptides and of MIG-14/Wls and the retromer complex in secreting EGL-20/WNT.