title: Betaine acts on a ligand-gated ion channel in the nervous system of the nematode C. elegans.
abstract: Prior to the advent of synthetic nematocides, natural products such as seaweed were used to control nematode infestations. The nematocidal agent in seaweed is betaine, an amino acid that functions as an osmolyte and methyl donor. However, the molecular mechanisms of betaine toxicity are unknown. We identified the betaine transporter SNF-3 and the betaine receptor ACR-23 in the nematode C. elegans. Mutating snf-3 in a sensitized background caused the worms to be hypercontracted and paralyzed, presumably as a result of excess extracellular betaine. These behavioral defects were suppressed by mutations in acr-23, which encodes a ligand-gated cation channel of the cys-loop family. ACR-23 was activated by betaine and functioned in the mechanosensory neurons to maintain basal levels of locomotion. However, overactivation of the receptor by excess betaine or by the allosteric modulator monepantel resulted in hypercontraction and death of the nematode. Thus, monepantel targets a betaine signaling pathway in nematodes.
authors.affiliation: 1] Department of Biology and Howard Hughes Medical Institute, University of Utah, Utah, USA. [2].
authors.forename: Aude S
authors.initials: AS
authors.lastname: Peden
authors.forename: Patrick
authors.initials: P
authors.lastname: Mac
authors.forename: You-Jun
authors.initials: YJ
authors.lastname: Fei
authors.forename: Cecilia
authors.initials: C
authors.lastname: Castro
authors.forename: Guoliang
authors.initials: G
authors.lastname: Jiang
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Murfitt
authors.forename: Eric A
authors.initials: EA
authors.lastname: Miska
authors.forename: Julian L
authors.initials: JL
authors.lastname: Griffin
authors.forename: Vadivel
authors.initials: V
authors.lastname: Ganapathy
authors.forename: Erik M
authors.initials: EM
authors.lastname: Jorgensen
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D000969:Antinematodal Agents / Q000378:metabolism / Q000494:pharmacology*; D001622:Betaine / Q000378:metabolism* / Q000494:pharmacology*; D049628:Body Size / Q000235:genetics; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects* / Q000235:genetics; D007814:Larva; D058446:Ligand-Gated Ion Channels / Q000235:genetics; D008465:Mechanoreceptors / Q000187:drug effects / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects; D009154:Mutation / Q000235:genetics; D009420:Nervous System / Q000378:metabolism*; D018377:Neurotransmitter Agents / Q000494:pharmacology; D011978:Receptors, Nicotinic / Q000235:genetics / Q000378:metabolism
chemical_list: C528080:ACR-23 protein, C elegans; D000969:Antinematodal Agents; D029742:Caenorhabditis elegans Proteins; D058446:Ligand-Gated Ion Channels; D018377:Neurotransmitter Agents; D011978:Receptors, Nicotinic; D049452:Green Fluorescent Proteins; D001622:Betaine