A novel anaerobic cholinergic signaling compound, β-alanine betaine, and nAChRs in Ascaris
- 1Department of Biomedical Sciences, Iowa State University, Ames, Iowa, United States of America
- 2Veterinary Diagnostic Laboratory, Iowa State University, Ames, Iowa, United States of America
- 3Department of Chemistry, Iowa State University, Ames, Iowa, United States of America
Abstract
Anthelmintic drugs are used to control soil-transmitted helminths that infect a quarter of the world’s human population. There is increasing concern about the development of resistance to anthelmintic drugs because of the limited number of compounds available and there is an unmet need for new resistance-busting drugs. Here we describe the presence of a previously unrecognized endogenous acetylcholine (ACh) analogue, β-alanine betaine, which may serve as an endogenous ligand for an alternate subfamily of nicotinic receptors (DEG-3/DES-2) that could be developed as novel drug targets because their analogues are not present in their human or animal hosts. We collected pseudocoelomic fluid from female Ascaris suum (a model for the human parasite Ascaris lumbricoides) and subjected it to HILIC-MS and HILIC-MS/MS to reveal signals consistent with ACh, choline, and β-alanine betaine but not betaine, propionylcholine, butyrylcholine, or butyrobetaine. The presence of β-alanine betaine was confirmed by comparison with an analytical standard. Injection of betaine into female A. suum produced no effect. However, injection of β-alanine betaine produced characteristic pretzel coiling and injection of levamisole produced a rod-like spastic paralysis. The differences between β-alanine betaine and levamisole suggested that they activate different nAChRs subfamilies. RT-PCR showed that message for members of the DEG-3/DES-2 subfamily of nAChR channels, which are betaine targets, were present in the intestine and body wall of A. suum. β-alanine betaine increased intracellular Ca2+ of the intestinal enterocytes and depolarized the membrane potential of body wall muscle cells. In N2 Caenorhabditis elegans, application of β-alanine betaine produced gradual inhibition of motility, which was reduced in acr-20, acr-23, deg-3/des-2 and lgc-41 null-mutants. These observations suggest that, in addition to ACh, β-alanine betaine - an analog of betaine produced under anaerobic conditions - may function as an endogenous ligand in anaerobic nematodes such as A. suum. An expanded repertoire of nicotinic acetylcholine receptor subfamilies in nematodes relative to mammals may reflect a corresponding need for diversification of cholinergic endogenous ligands in these organisms. This repertoire could allow their simpler neuronal system to perform more complex controls and be exploited for development of different and novel subfamily selective cholinergic anthelmintics. Author summary: There is increasing concern about the development of resistance to anthelmintic drugs because of the limited number of compounds available and there is an unmet need for new resistance-busting drugs. The cholinergic anthelmintics are one of the three major classes of anti-nematodal drugs that are used for control and treatment of soil-transmitted helminths. Each of these cholinergic anthelmintics (levamisole, pyrantel, derquantel, monepantel and oxantel) are selective for different nematode nicotinic acetylcholine receptors (nAChRs). The differences in selectivity could explain why resistance and species sensitivities varies across the different cholinergic anthelmintics. It is surprising how many nAChR genes are expressed in nematodes with more being present compared to humans. Why is this? Could it be that there are also more endogenous ligands other than ACh allowing their simpler neuronal system to perform more complex control? We looked for additional analogues of ACh in the body fluid of the large intestinal pig parasite, Ascaris suum, (a model for Ascaris lumbricoides) and identified the anaerobic cholinergic compound β-alanine betaine. We found evidence that suggests that β-alanine betaine may serve as an endogenous ligand for an alternate subfamily of nicotinic receptors (DEG-3/DES-2) that could be developed as novel drug targets because their receptor analogues are not present in human or animal hosts.
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BibTeX
@article{williams2026novel,
title = {{A novel anaerobic cholinergic signaling compound, β-alanine betaine, and nAChRs in Ascaris}},
author = {Paul D. E. Williams and David J. Borts and Dongjie Liu and Jacob Byerley-Duke and Brett VanVeller and Richard J. Martin},
journal = {PLOS Neglected Tropical Diseases},
year = {2026},
month = sep,
doi = {10.1371/journal.pntd.0014518},
url = {https://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0014518},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - A novel anaerobic cholinergic signaling compound, β-alanine betaine, and nAChRs in Ascaris
AU - Paul D. E. Williams
AU - David J. Borts
AU - Dongjie Liu
AU - Jacob Byerley-Duke
AU - Brett VanVeller
AU - Richard J. Martin
PY - 2026
DA - 2026/09/08
JO - PLOS Neglected Tropical Diseases
DO - 10.1371/journal.pntd.0014518
UR - https://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0014518
AB - Anthelmintic drugs are used to control soil-transmitted helminths that infect a quarter of the world’s human population. There is increasing concern about the development of resistance to anthelmintic drugs because of the limited number of compounds available and there is an unmet need for new resistance-busting drugs. Here we describe the presence of a previously unrecognized endogenous acetylcholine (ACh) analogue, β-alanine betaine, which may serve as an endogenous ligand for an alternate subfamily of nicotinic receptors (DEG-3/DES-2) that could be developed as novel drug targets because their analogues are not present in their human or animal hosts. We collected pseudocoelomic fluid from female Ascaris suum (a model for the human parasite Ascaris lumbricoides) and subjected it to HILIC-MS and HILIC-MS/MS to reveal signals consistent with ACh, choline, and β-alanine betaine but not betaine, propionylcholine, butyrylcholine, or butyrobetaine. The presence of β-alanine betaine was confirmed by comparison with an analytical standard. Injection of betaine into female A. suum produced no effect. However, injection of β-alanine betaine produced characteristic pretzel coiling and injection of levamisole produced a rod-like spastic paralysis. The differences between β-alanine betaine and levamisole suggested that they activate different nAChRs subfamilies. RT-PCR showed that message for members of the DEG-3/DES-2 subfamily of nAChR channels, which are betaine targets, were present in the intestine and body wall of A. suum. β-alanine betaine increased intracellular Ca2+ of the intestinal enterocytes and depolarized the membrane potential of body wall muscle cells. In N2 Caenorhabditis elegans, application of β-alanine betaine produced gradual inhibition of motility, which was reduced in acr-20, acr-23, deg-3/des-2 and lgc-41 null-mutants. These observations suggest that, in addition to ACh, β-alanine betaine - an analog of betaine produced under anaerobic conditions - may function as an endogenous ligand in anaerobic nematodes such as A. suum. An expanded repertoire of nicotinic acetylcholine receptor subfamilies in nematodes relative to mammals may reflect a corresponding need for diversification of cholinergic endogenous ligands in these organisms. This repertoire could allow their simpler neuronal system to perform more complex controls and be exploited for development of different and novel subfamily selective cholinergic anthelmintics. Author summary: There is increasing concern about the development of resistance to anthelmintic drugs because of the limited number of compounds available and there is an unmet need for new resistance-busting drugs. The cholinergic anthelmintics are one of the three major classes of anti-nematodal drugs that are used for control and treatment of soil-transmitted helminths. Each of these cholinergic anthelmintics (levamisole, pyrantel, derquantel, monepantel and oxantel) are selective for different nematode nicotinic acetylcholine receptors (nAChRs). The differences in selectivity could explain why resistance and species sensitivities varies across the different cholinergic anthelmintics. It is surprising how many nAChR genes are expressed in nematodes with more being present compared to humans. Why is this? Could it be that there are also more endogenous ligands other than ACh allowing their simpler neuronal system to perform more complex control? We looked for additional analogues of ACh in the body fluid of the large intestinal pig parasite, Ascaris suum, (a model for Ascaris lumbricoides) and identified the anaerobic cholinergic compound β-alanine betaine. We found evidence that suggests that β-alanine betaine may serve as an endogenous ligand for an alternate subfamily of nicotinic receptors (DEG-3/DES-2) that could be developed as novel drug targets because their receptor analogues are not present in human or animal hosts.
SN - 1935-2735
ER -