scholarly journals The Caenorhabditis elegans DEG-3/DES-2 Channel Is a Betaine-Gated Receptor Insensitive to Monepantel

Molecules ◽  
2022 ◽  
Vol 27 (1) ◽  
pp. 312
Author(s):  
Tina V. A. Hansen ◽  
Heinz Sager ◽  
Céline E. Toutain ◽  
Elise Courtot ◽  
Cédric Neveu ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Parasitic Nematode ◽  
Nematode Species ◽  
Xenopus Laevis Oocytes ◽  
Allosteric Modulators ◽  
C Elegans ◽  
Electrode Voltage ◽  
Insight Into

Natural plant compounds, such as betaine, are described to have nematocidal properties. Betaine also acts as a neurotransmitter in the free-living model nematode Caenorhabditis elegans, where it is required for normal motility. Worm motility is mediated by nicotinic acetylcholine receptors (nAChRs), including subunits from the nematode-specific DEG-3 group. Not all types of nAChRs in this group are associated with motility, and one of these is the DEG-3/DES-2 channel from C. elegans, which is involved in nociception and possibly chemotaxis. Interestingly, the activity of DEG-3/DES-2 channel from the parasitic nematode of ruminants, Haemonchus contortus, is modulated by monepantel and its sulfone metabolite, which belong to the amino-acetonitrile derivative anthelmintic drug class. Here, our aim was to advance the pharmacological knowledge of the DEG-3/DES-2 channel from C. elegans by functionally expressing the DEG-3/DES-2 channel in Xenopus laevis oocytes and using two-electrode voltage-clamp electrophysiology. We found that the DEG-3/DES-2 channel was more sensitive to betaine than ACh and choline, but insensitive to monepantel and monepantel sulfone when used as direct agonists and as allosteric modulators in co-application with betaine. These findings provide important insight into the pharmacology of DEG-3/DES-2 from C. elegans and highlight the pharmacological differences between non-parasitic and parasitic nematode species.

The use of Caenorhabditis elegans in parasitic nematode research

Parasitology ◽  
2004 ◽  
Vol 128 (S1) ◽  
pp. S49-S70 ◽  
Author(s):  
J. S. GILLEARD
Keyword(s):  
Caenorhabditis Elegans ◽  
Parasitic Nematode ◽  
Expression System ◽  
Nematode Species ◽  
Current Status ◽  
Evolutionary Development ◽  
Parasitic Nematodes ◽  
Free Living ◽  
C Elegans ◽  
Free Living Nematode

There is increasing interest in the use of the free-living nematode Caenorhabditis elegans as a tool for parasitic nematode research and there are now a number of compelling examples of its successful application. C. elegans has the potential to become a standard tool for molecular helminthology researchers, just as yeast is routinely used by molecular biologists to study vertebrate biology. However, in order to exploit C. elegans in a meaningful manner, we need a detailed understanding of the extent to which different aspects of C. elegans biology have been conserved with particular groups of parasitic nematodes. This review first considers the current state of knowledge regarding the conservation of genome organisation across the nematode phylum and then discusses some recent evolutionary development studies in free-living nematodes. The aim is to provide some important concepts that are relevant to the extrapolation of information from C. elegans to parasitic nematodes and also to the interpretation of experiments that use C. elegans as a surrogate expression system. In general, examples have been specifically chosen because they highlight the importance of careful experimentation and interpretation of data. Consequently, the focus is on the differences that have been found between nematode species rather than the similarities. Finally, there is a detailed discussion of the current status of C. elegans as a heterologous expression system to study parasite gene function and regulation using successful examples from the literature.

scholarly journals Tetrapeptide Ac-HAEE-NH2 Protects α4β2 nAChR from Inhibition by Aβ

2020 ◽  
Vol 21 (17) ◽  
pp. 6272
Author(s):  
Evgeny P. Barykin ◽  
Aleksandra I. Garifulina ◽  
Anna P. Tolstova ◽  
Anastasia A. Anashkina ◽  
Alexei A. Adzhubei ◽  
...  
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Cholinergic Neurons ◽  
Xenopus Laevis Oocytes ◽  
Aβ Peptide ◽  
Amino Acid Residues ◽  
Cholinergic Dysfunction ◽  
Potential Binding ◽  
Electrode Voltage ◽  
Potential Binding Site

The cholinergic deficit in Alzheimer’s disease (AD) may arise from selective loss of cholinergic neurons caused by the binding of Aβ peptide to nicotinic acetylcholine receptors (nAChRs). Thus, compounds preventing such an interaction are needed to address the cholinergic dysfunction. Recent findings suggest that the 11EVHH14 site in Aβ peptide mediates its interaction with α4β2 nAChR. This site contains several charged amino acid residues, hence we hypothesized that the formation of Aβ-α4β2 nAChR complex is based on the interaction of 11EVHH14 with its charge-complementary counterpart in α4β2 nAChR. Indeed, we discovered a 35HAEE38 site in α4β2 nAChR, which is charge-complementary to 11EVHH14, and molecular modeling showed that a stable Aβ42-α4β2 nAChR complex could be formed via the 11EVHH14:35HAEE38 interface. Using surface plasmon resonance and bioinformatics approaches, we further showed that a corresponding tetrapeptide Ac-HAEE-NH2 can bind to Aβ via 11EVHH14 site. Finally, using two-electrode voltage clamp in Xenopus laevis oocytes, we showed that Ac-HAEE-NH2 tetrapeptide completely abolishes the Aβ42-induced inhibition of α4β2 nAChR. Thus, we suggest that 35HAEE38 is a potential binding site for Aβ on α4β2 nAChR and Ac-HAEE-NH2 tetrapeptide corresponding to this site is a potential therapeutic for the treatment of α4β2 nAChR-dependent cholinergic dysfunction in AD.

scholarly journals Acetylcholine Signaling Genes are Required for Cocaine-Stimulated Egg Laying in Caenorhabditis elegans

2020 ◽  
Author(s):  
Soren Emerson ◽  
Megan Hay ◽  
Mark Smith ◽  
David Blauch ◽  
Nicole Snyder ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Nicotinic Acetylcholine Receptors ◽  
Intracellular Signaling ◽  
Acetylcholine Receptors ◽  
Egg Laying ◽  
Synthetic Enzymes ◽  
C Elegans ◽  
Degradative Enzymes ◽  
Serotonin Reuptake Transporter

Despite the toxicity and addictive liability associated with cocaine abuse, its mode of action is not completely understood, and effective pharmacotherapeutic interventions remain elusive. The cholinergic effects of cocaine on acetylcholine receptors, synthetic enzymes, and degradative enzymes have been the focus of relatively little empirical investigation. Due to its genetic tractability and anatomical simplicity, the egg laying circuit of the hermaphroditic nematode, Caenorhabditis elegans, is a powerful model system to precisely examine the genetic and molecular targets of cocaine in vivo. Here, we report a novel cocaine-induced phenotype in Caenorhabditis elegans, cocaine-stimulated egg laying. In addition, we present the results of an in vivo candidate screen of synthetic enzymes, receptors, degradative enzymes, and downstream components of the intracellular signaling cascades of the main neurotransmitter systems that control Caenorhabditis elegans egg laying. Our results show that cocaine-stimulated egg laying is dependent on acetylcholine synthesis and synaptic release, functional nicotinic acetylcholine receptors, and the Caenorhabditis elegans acetylcholinesterases. Further, we show that cocaine-stimulated egg laying is not dependent on other neurotransmitters besides acetylcholine, including serotonin, dopamine, octopamine, and tyramine. Finally, our data show that cocaine-stimulated egg laying is increased in mutants for the C. elegans serotonin reuptake transporter as well as mutants for a 5-HT-gated chloride channel likely expressed in the locomotion circuit. Together, these results highlight serotonergic inhibition of egg laying behavior, functional connectivity between the egg laying and locomotion circuits in Caenorhabditis elegans, and possible discrete cholinergic and serotonergic effects of cocaine in the egg laying and locomotion circuits, respectively.

Mode of action of levamisole and pyrantel, anthelmintic resistance, E153 and Q57

Parasitology ◽  
2007 ◽  
Vol 134 (8) ◽  
pp. 1093-1104 ◽  
Author(s):  
R. J. MARTIN ◽  
A. P. ROBERTSON
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Nicotinic Receptors ◽  
Anthelmintic Resistance ◽  
Nematode Species ◽  
Single Mutation ◽  
Somatic Muscle ◽  
Nicotinic Acetylcholine ◽  
C Elegans ◽  
Molecular Information

SUMMARYHere we review molecular information related to resistance to the cholinergic anthelmintics in nematodes. The amount of molecular information available varies between the nematode species, with the best understood so far being C. elegans. More information is becoming available for some other parasitic species. The cholinergic anthelmintics act on nematode nicotinic acetylcholine receptors located on somatic muscle cells. Recent findings demonstrate the presence of multiple types of the nicotinic receptors in several nematodes and the numerous genes required to form these multimeric proteins. Not only are the receptors the product of several genes but they are subject to modulation by several other proteins. Mutations altering these modulatory proteins could alter sensitivity to the cholinergic anthelmitics and thus lead to resistance. We also discuss the possibility that resistance to the cholinergic anthelmintics is not necessarily the result of a single mutation but may well be polygenic in nature. Additionally, the mutations resulting in resistance may vary between different species or between resistant isolates of the same species. A list of candidate genes to examine for SNPs is presented.

scholarly journals RIC-3 phosphorylation enables dual regulation of excitation and inhibition of Caenorhabditis elegans muscle

2016 ◽  
Vol 27 (19) ◽  
pp. 2994-3003 ◽  
Author(s):  
Gracia Safdie ◽  
Jana F. Liewald ◽  
Sarah Kagan ◽  
Emil Battat ◽  
Alexander Gottschalk ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Motor Neurons ◽  
Nicotinic Acetylcholine Receptors ◽  
Brain Function ◽  
Acetylcholine Receptors ◽  
Fine Tuning ◽  
Dual Effect ◽  
C Elegans ◽  
Receptor Inhibition ◽  
Muscle Excitability

Brain function depends on a delicate balance between excitation and inhibition. Similarly, Caenorhabditis elegans motor system function depends on a precise balance between excitation and inhibition, as C. elegans muscles receive both inhibitory, GABAergic and excitatory, cholinergic inputs from motor neurons. Here we show that phosphorylation of the ER-resident chaperone of nicotinic acetylcholine receptors, RIC-3, leads to increased muscle excitability. RIC-3 phosphorylation at Ser-164 depends on opposing functions of the phosphatase calcineurin (TAX-6), and of the casein kinase II homologue KIN-10. Effects of calcineurin down-regulation and of phosphorylated RIC-3 on muscle excitability are mediated by GABAA receptor inhibition. Thus RIC-3 phosphorylation enables effects of this chaperone on GABAA receptors in addition to nAChRs. This dual effect provides coordinated regulation of excitation and inhibition and enables fine-tuning of the excitation–inhibition balance. Moreover, regulation of inhibitory GABAA signaling by calcineurin, a calcium- and calmodulin-dependent phosphatase, enables homeostatic balancing of excitation and inhibition.

Lophotoxin-insensitive nematode nicotinic acetylcholine receptors.

1996 ◽  
Vol 199 (10) ◽  
pp. 2161-2168
Author(s):  
C Tornøe ◽  
L Holden-Dye ◽  
C Garland ◽  
S N Abramson ◽  
J T Fleming ◽  
...  
Keyword(s):  
Xenopus Laevis ◽  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Ascaris Suum ◽  
Xenopus Laevis Oocytes ◽  
Nicotinic Acetylcholine ◽  
Mouse Muscle ◽  
C Elegans ◽  
Naturally Occurring ◽  
Alpha Bungarotoxin

Nematode nicotinic acetylcholine receptors (nAChRs) are molecular targets of several anthelmintic drugs. Studies to date on Caenorhabditis elegans and Ascaris suum have demonstrated atypical pharmacology with respect to nAChR antagonists, including the finding that kappa-bungarotoxin is a more effective antagonist than alpha-bungarotoxin on Ascaris muscle nAChRs. Lophotoxin and its naturally occurring analogue bipinnatin B block all vertebrate and invertebrate nAChRs so far examined. In the present study, the effects on nematode nAChRs of bipinnatin B have been examined. The Ascaris suum muscle cell nAChR was found to be insensitive to 30 mumol l-1 bipinnatin B, a concentration that is highly effective on other nAChRs. To our knowledge, this is the first demonstration of a nAChR that is insensitive to one of the lophotoxins. Xenopus laevis oocytes injected with C. elegans polyadenylated, poly(A+), mRNA also expressed bipinnatin-B-insensitive levamisole responses, which were, however, blocked by the nAChR antagonist mecamylamine (10 mumol l-1). In contrast to the findings for nematode receptors, bipinnatin B (30 mumol l-1) was effective in blocking mouse muscle nAChRs expressed in Xenopus laevis oocytes and native insect nAChRs. A possible explanation for insensitivity of certain nematode nAChRs to lophotoxins is advanced based on the sequence of an alpha-like C. elegans nAChR subunit in which tyrosine-190 (numbering based on the Torpedo californica sequence), a residue known to be critical for lophotoxin binding in vertebrate nAChRs, is replaced by a proline residue.

scholarly journals A survey of the kinome pharmacopeia reveals multiple scaffolds and targets for the development of novel anthelmintics

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jessica Knox ◽  
Nicolas Joly ◽  
Edmond M. Linossi ◽  
José A. Carmona-Negrón ◽  
Natalia Jura ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Developmental Delay ◽  
Small Molecule ◽  
Parasitic Nematode ◽  
Kinase Inhibitor ◽  
Binding Pocket ◽  
Drug Binding ◽  
Nematode Infection ◽  
Selective Inhibitors ◽  
C Elegans

AbstractOver one billion people are currently infected with a parasitic nematode. Symptoms can include anemia, malnutrition, developmental delay, and in severe cases, death. Resistance is emerging to the anthelmintics currently used to treat nematode infection, prompting the need to develop new anthelmintics. Towards this end, we identified a set of kinases that may be targeted in a nematode-selective manner. We first screened 2040 inhibitors of vertebrate kinases for those that impair the model nematode Caenorhabditis elegans. By determining whether the terminal phenotype induced by each kinase inhibitor matched that of the predicted target mutant in C. elegans, we identified 17 druggable nematode kinase targets. Of these, we found that nematode EGFR, MEK1, and PLK1 kinases have diverged from vertebrates within their drug-binding pocket. For each of these targets, we identified small molecule scaffolds that may be further modified to develop nematode-selective inhibitors. Nematode EGFR, MEK1, and PLK1 therefore represent key targets for the development of new anthelmintic medicines.

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