LEV-10 and NRA-2 regulate distinct mechanisms of cholinergic tachyphylaxis in Caenorhabditis elegans
Abstract
Soil-transmitted helminthiasis affects more than a billion people worldwide and is a global health concern. With no effective vaccination available, treatment relies on mass administration of anthelmintic drugs, like albendazole, ivermectin, and levamisole. Unfortunately, their regular of overuse has given rise to resistance. Levamisole, a cholinergic agonist, activates the nematode L-type acetylcholine receptors and causes muscle contraction and worm paralysis. In parasitic nematodes, such as female Brugia malayi , worms paralyze and recover through cholinergic tachyphylaxis. In this study, we dissect the molecular mechanisms behind cholinergic tachyphylaxis using the free-living model, C. elegans . Here, we differentiate between two independent recovery mechanisms: one that is mediated by L-AChR clustering mutants – lev-10 and another, mediated by an ER-resident protein, NRA-2. Cholinergic tachyphylaxis observed in nra-2 mutants can be distinguished from lev-10 mutants using motility assays, transcript analysis, and calcium imaging. nra-2 mutants are more sensitive to levamisole and recover differently than lev-10 mutants. We observe that nra-2 mutants do not show increased calcium influx during their levamisole-mediated recovery. Our study delineates two distinct modes by which worms can adapt and overcome effects of cholinergic anthelmintics.
Related
- The Endogenous Negative Allosteric Modulator, Lynx1, Inhibits Nicotinic Cholinergic Signaling in the Ventral Tegmental Area to Regulate Nicotine Reinforcement
- Multiple mechanisms cooperate to control PUF protein FBF-1 and FBF-2 accumulation in Caenorhabditis elegans germline
- AXIN1 and AXIN2 regulate the WNT-signaling landscape to promote distinct mesoderm programs
- The transcription factor PRO44 and the histone chaperone ASF1 regulate distinct aspects of multicellular development in the filamentous fungus Sordaria macrospora.
- Natural products regulate gut microbiota and SCFA metabolism in IBD: mechanisms and therapeutic potential
BibTeX
@misc{gupta2026lev10,
title = {{LEV-10 and NRA-2 regulate distinct mechanisms of cholinergic tachyphylaxis in Caenorhabditis elegans}},
author = {Shruti Gupta and Jacob Wragge and Sudhanva Kashyap},
howpublished = {Research Square},
year = {2026},
month = oct,
doi = {10.21203/rs.3.rs-11130925/v1},
url = {https://doi.org/10.21203/rs.3.rs-11130925/v1},
note = {CC BY 4.0},
}
RIS
TY - UNPB
TI - LEV-10 and NRA-2 regulate distinct mechanisms of cholinergic tachyphylaxis in Caenorhabditis elegans
AU - Shruti Gupta
AU - Jacob Wragge
AU - Sudhanva Kashyap
PY - 2026
DA - 2026/10/27
PB - Research Square
DO - 10.21203/rs.3.rs-11130925/v1
UR - https://doi.org/10.21203/rs.3.rs-11130925/v1
AB - Soil-transmitted helminthiasis affects more than a billion people worldwide and is a global health concern. With no effective vaccination available, treatment relies on mass administration of anthelmintic drugs, like albendazole, ivermectin, and levamisole. Unfortunately, their regular of overuse has given rise to resistance. Levamisole, a cholinergic agonist, activates the nematode L-type acetylcholine receptors and causes muscle contraction and worm paralysis. In parasitic nematodes, such as female Brugia malayi , worms paralyze and recover through cholinergic tachyphylaxis. In this study, we dissect the molecular mechanisms behind cholinergic tachyphylaxis using the free-living model, C. elegans . Here, we differentiate between two independent recovery mechanisms: one that is mediated by L-AChR clustering mutants – lev-10 and another, mediated by an ER-resident protein, NRA-2. Cholinergic tachyphylaxis observed in nra-2 mutants can be distinguished from lev-10 mutants using motility assays, transcript analysis, and calcium imaging. nra-2 mutants are more sensitive to levamisole and recover differently than lev-10 mutants. We observe that nra-2 mutants do not show increased calcium influx during their levamisole-mediated recovery. Our study delineates two distinct modes by which worms can adapt and overcome effects of cholinergic anthelmintics.
SN - 2693-5015
ER -