Peptidases and Neuropeptide Processing

Methods in Neurosciences: Peptidases and Neuropeptide Processing

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The decision to enter reproductive growth after hatching is dependent on the activity of DAF-2 , an insulin-like receptor, and ASNA-1 , an ATPase that acts non-cell autonomously and regulates the insulin pathway see below; Gems et al. Under continued exposure to harsh environmental conditions, such as overcrowding, high temperatures, or a scarce food supply during L1 or L2, C.

After L2, animals enter the dauer state rather than L3 and remain in the dauer state until conditions improve, whereupon they exit the dauer state and resume the lifecycle as L4 animals Cassada and Russell, Loss of either pathway results in constitutive dauer formation, indicating that the pathways function independently. DAF-2 also functions to determine lifespan Kenyon et al.

DAF-2 is the closest homologue to the mammalian insulin-like receptor superfamily Kimura et al. Members of the insulin superfamily are encoded by the ins genes and daf in C. Only two insulin-family genes that have been inactivated by mutation have been examined thus far. INS-1 is most similar to mammalian insulin Pierce et al.

Loss of ins-1 has no effect on dauer formation or longevity Pierce et al. By contrast, the daf sa mutation causes transient dauer formation Malone and Thomas, The mutation is likely to act as a dominant negative whereby the daf sa gene product antagonizes DAF-2 activity Li et al. Consistent with this hypothesis, levels of a P daf ::GFP transgene are decreased during starvation or application of dauer pheromone Li et al. Expression of the P daf ::GFP transgene is found in an increasing number of cells as the animal ages Li et al.

If other insulin-like peptides also signal through the DAF-2 receptor, then perturbations of other ins genes may enhance or suppress the phenotypes of daf-2 and daf mutants. The phenotypes caused by overexpression of several ins genes, using their endogenous promoters, were examined in different daf backgrounds. However, overexpression of ins-9 or of ins and ins in combination in a wild-type or daf-2 mutant background caused embryonic or larval arrest, a phenotype similar to one shown by some daf-2 alleles Pierce et al.

Overexpression of ins-4 or ins-6 can suppress or partially suppress, respectively, the daf sa mutation, suggesting that INS-4 or INS-6 can functionally substitute for DAF and activate the DAF-2 receptor when present at high levels Li et al. By contrast, overexpression of ins-7 , 9 , 17 , 21 , 22 , and 23 did not suppress the daf sa mutation Li et al. These data indicate that several insulin-like ligands signal through or affect DAF-2 activity to affect developmental growth and dauer formation, while other insulin-like ligands signal through other non-DAF-2 insulin receptors.

What are the roles of the other ins genes? Until mutants are isolated, the function of this large class of neuropeptides is largely unknown. Recently, INS-1 was identified as a key neuropeptide in the integration of behavior with the functional state of the animal.

Sleep, neuropeptides and proteases

When placed on a thermal gradient well-fed animals move towards the temperature on which they were cultivated, whereas starved animals avoid the temperature at which they were cultivated Hedgecock and Russell, Well-fed ins-1 mutants exhibit normal thermotaxis, indicating that the basic thermosensory properties of AFD are intact in the mutants.

Similar to starved wild-type animals, starved ins-1 animals slow when encountering food, demonstrating that ins-1 animals can recognize their starvation state Kodama et al. However, starved ins-1 mutants move towards rather than away from their cultivation temperature, presumably because they cannot integrate cultivation temperature with starvation state Kodama et al. This integration defect can be rescued by expression of ins-1 in different neurons and is partially suppressed by mutations in daf-2 and age-1 , suggesting that INS-1 acts non-cell autonomously to antagonize signaling through the DAF-2 receptor Kodama et al.

Wild-type animals normally chemotax towards sodium chloride NaCl Ward, However, after pre-exposure to NaCl, starved, but not well-fed animals will avoid NaCl; this behavior is referred to as salt chemotaxis learning Saeki et al. Several mutants, including daf-2 , age-1 , pdk-1 , akt-1 , and ins-1 , are defective for salt chemotaxis learning Tomioka et al. Hence, INS-1 is involved in multiple integration events and whether it activates or antagonizes DAF-2 signaling is context dependent.

Social Network Confirmation

Acetylcholine is the primary excitatory transmitter at the neuromuscular junction in C. Aldicarb blocks the effects of acetylcholinesterase, thereby increasing the amount of acetylcholine at the synapse and causing paralysis and lethality Nguyen et al. To identify genes that are resistant to aldicarb, a genome-wide RNAi screen was performed on eri-1 ;linB or eri-1 ; dgk-1 linB mutants, which have a sensitized background for RNAi Sieburth et al. In addition to the processing enzymes, decreased activity of four neuropeptide genes, two ins genes ins and ins , one flp gene flp-1 , and one nlp gene nlp , conferred aldicarb-resistance, suggesting that the peptides encoded by these genes modulate acetylcholine signaling Sieburth et al.

Table of Contents

Deletion mutants have been isolated for eleven flp genes Nelson et al. Inactivation of flp-1 causes several defects, including hyperactive movement Nelson et al. Ashrafi, pers. FLP-1 peptides are also necessary for down-regulation of egg laying in the absence of food Waggoner et al. The remaining flp mutants are currently being examined. Because so many flp genes have overlapping expression patterns, the function of these genes may also overlap and, therefore, be difficult to tease apart. Hence, deletion mutants are being screened on a large variety of behavioral assays. For instance, the swimming or thrashing assay, which involves placing animals in physiological buffer and counting the number of thrashes per minute, is more sensitive for detecting locomotion defects than examining the animal's movement on a solid surface.

By the thrashing assay, flp-9 was found to thrash significantly less actively than wild-type animals unpubl. Hence, to understand how the FLPs function, mutants will be examined for subtle defects, animals carrying multiple knockouts need to be isolated, and the receptor to which the peptides bind must be identified, as was done in the case of flp The function of flp will be discussed in conjunction with the function of its receptor, NPR Although no nlp mutant has been examined thus far, several of the nlp genes may function as anti-microbial peptides.

In microarray analyses to identify genes whose expression levels are changed in response to fungal or bacterial insults, expression of nlp , 31 , and 33 was induced Couillault et al.

Furthermore, the peptide encoded by nlp has anti-microbial activity and protects against fungal infection Couillault et al. The peptides encoded by nlp , 25 , 27 , 28 , and 30 are similar to those encoded by nlp , 31 , and 33 , suggesting that these peptides also have anti-microbial functions Couillault et al. By contrast, nlp and 27 are also expressed in neurons Nathoo et al.

The expression patterns of nlp and 28 are unknown, so whether the peptides encoded by these genes also function as anti-microbial agents is unknown. As described above, nlp is involved in modulating acetylcholine signaling Sieburth et al. As mentioned above, the function of a specific neuropeptide may be difficult to discern. Not only are multiple neuropeptides expressed in a single cell, but a specific neuropeptide may bind to multiple receptors.

As illustrated above with the insulin-like peptides and their receptors, an alternative strategy to determine the function of neuropeptides is to inactivate the receptors to which the peptides bind.

Of the G-protein-coupled receptors in C. Sixty G-protein receptors that were predicted to bind either a small molecule transmitter or a neuropeptide were inactivated by RNAi and screened for behavioral deficits Keating et al. RNAi of six receptors, C16D6. The phenotypes from the RNAi data were confirmed in two cases by the isolation of deletion mutants in T05A1.

Several of the ligands for these receptors have now been identified see below. To match FLP ligands to specific G protein-coupled receptor binding partners, several groups have expressed candidate receptors in either heterologous cells or Xenopus oocytes Kubiak et al.

Different FLP ligands were applied and several assays were used as the read out. Some of the receptors are activated by multiple peptides encoded by one gene, while other receptors can be activated by peptides encoded by different genes. A few examples will be described below. Binding of the cognate ligand to the receptor would presumably activate the receptor, thereby activating G proteins.

Nevertheless, Mertens and co-workers found that C26F1. A FLP receptor can also bind to a diverse group of peptides with a range of activities. The Y59H11AL.

Limited neuropeptide Y precursor processing in unfavourable metastatic neuroblastoma tumours

Note that peptides encoded by flp-7 bind to two receptors, C26F1. Where these two receptors are expressed may give us some clues as to how FLP-7 peptides affect behavior. Given that a FLP receptor can bind to multiple peptides encoded by different genes and a single peptide can bind to multiple receptors, the potential complexity of peptide actions in C. Mutations in the NPR-1 receptor affect aggregation behavior de Bono and Bargmann, and tolerance to alcohol Davies et al. On an agar plate with a bacterial food source, wild-type animals feed alone referred to as solitary feeding ; a mutation in npr-1 causes the animals to aggregate during feeding referred to as social feeding and accumulate at the edges of the bacteria referred to as bordering behavior; de Bono and Bargmann, The aggregation behavior of npr-1 mutants can be suppressed by mutations in gcy or gcy Cheung et al.

GCY guanylate cyclase binds oxygen, and the aggregation behavior of npr-1 mutants may be related to oxygen levels in the local environment of the animals Gray et al. To identify the NPR-1 ligand, the de Bono group injected constructs for NPR-1 as well as inwardly rectifying potassium channels into Xenopus oocytes, and screened for receptor activation of the potassium channels Rogers et al. Because no neuropeptide Y is present in C. Both Rogers et al. Animals carrying a mutation in flp display only mild aggregation compared to npr-1 mutants Rogers et al.

Two explanations may account for the difference in phenotypes between the FLP ligand and the NPR-1 receptor mutants. The first is that the flp mutation may be a partial loss of function allele instead of a null allele; the second is that FLP ligands, which also bind NPR-1 , may functionally substitute for the loss of FLP ligands Rogers et al.

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