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A C. elegans genome-wide RNAi screen for altered levamisole sensitivity identifies genes required for muscle function
- Source :
- G3: Genes, Genomes, Genetics, Vol 11, Iss 4 (2021), G3: Genes|Genomes|Genetics
- Publication Year :
- 2021
- Publisher :
- Oxford University Press, 2021.
-
Abstract
- At the neuromuscular junction (NMJ), postsynaptic ionotropic acetylcholine receptors (AChRs) transduce a chemical signal released from a cholinergic motor neuron into an electrical signal to induce muscle contraction. To identify regulators of postsynaptic function, we conducted a genome-wide RNAi screen for genes required for proper response to levamisole, a pharmacological agonist of ionotropic L-AChRs at the Caenorhabditis elegans NMJ. A total of 117 gene knockdowns were found to cause levamisole hypersensitivity, while 18 resulted in levamisole resistance. Our screen identified conserved genes important for muscle function including some that are mutated in congenital myasthenic syndrome, congenital muscular dystrophy, congenital myopathy, myotonic dystrophy, and mitochondrial myopathy. Of the genes found in the screen, we further investigated those predicted to play a role in endocytosis of cell surface receptors. Loss of the Epsin homolog epn-1 caused levamisole hypersensitivity and had opposing effects on the levels of postsynaptic L-AChRs and GABAA receptors, resulting in increased and decreased abundance, respectively. We also examined other genes that resulted in a levamisole-hypersensitive phenotype when knocked down including gas-1, which functions in Complex I of the mitochondrial electron transport chain. Consistent with altered ATP synthesis impacting levamisole response, treatment of wild-type animals with levamisole resulted in L-AChR–dependent depletion of ATP levels. These results suggest that the paralytic effects of levamisole ultimately lead to metabolic exhaustion.
- Subjects :
- AcademicSubjects/SCI01140
animal structures
AcademicSubjects/SCI00010
QH426-470
AcademicSubjects/SCI01180
Neuromuscular junction
GABA
03 medical and health sciences
0302 clinical medicine
gas-1
Postsynaptic potential
medicine
Genetics
Animals
endocytosis
Caenorhabditis elegans
Caenorhabditis elegans Proteins
Receptor
Molecular Biology
Genetics (clinical)
030304 developmental biology
Acetylcholine receptor
0303 health sciences
levamisole
biology
Muscles
Mutant Screen Report
Levamisole
Congenital myasthenic syndrome
biology.organism_classification
medicine.disease
acetylcholine
epn-1
Cell biology
ATP
medicine.anatomical_structure
C. elegans
AcademicSubjects/SCI00960
RNA Interference
030217 neurology & neurosurgery
medicine.drug
Ionotropic effect
Subjects
Details
- Language :
- English
- ISSN :
- 21601836
- Volume :
- 11
- Issue :
- 4
- Database :
- OpenAIRE
- Journal :
- G3: Genes, Genomes, Genetics
- Accession number :
- edsair.doi.dedup.....ebbe6090af739413ab0f66f619d258c3