Caenorhabditis elegansLevamisole Resistance Geneslev-1,unc-29, andunc-38Encode Functional Nicotinic Acetylcholine Receptor Subunits

Fleming, John T.; Squire, Michael D.; Barnes, Thomas M.; Tornoe, C.; Matsuda, Kazuhiko; Ahnn, Joohong; Fire, Andrew; Sulston, John; Barnard, Eric A.; Sattelle, David B.; Lewis, James A.

doi:10.1523/jneurosci.17-15-05843.1997

Cited by 309 publications

(298 citation statements)

References 94 publications

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“…unc-29 and lev-1 encode non-alpha subunits of nAChRs, and UNC-29 and LEV-1 proteins are required for normal locomotion, regulation of egglaying behavior, and formation of a cation channel expressed with UNC-38. 21,31) In the present study, the inability of nicotine to augment gustatory plasticity in both unc-29 and lev-1 mutants was observed (Fig. 4).…”

Section: Involvement Of Dopamine Signaling Pathway In the Effects Of supporting

confidence: 59%

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Chronic nicotine exposure augments gustatory plasticity inCaenorhabditis elegans:involvement of dopamine signaling

Matsuura

Urushihata

2015

Bioscience, Biotechnology, and Biochemistry

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The chemotaxis of wild-type NaCl-conditioned nematodes exposed to 100 mM NaCl, maintained on a growth medium containing 0.3 mM nicotine from first larva to young adult (YA) hermaphrodite, was significantly weaker than the chemotaxis of those maintained on a medium without nicotine. The result indicates that chronic nicotine exposure augments gustatory plasticity. The gustatory plasticity was also augmented when tph-1 mutants, with a defect in serotonin biosynthesis, were maintained on a medium containing nicotine until the YA stage. Chronic nicotine exposure did not augment gustatory plasticity in bas-1 mutants, which had defects in both serotonin and dopamine biosynthesis, and in cat-2 mutants, which had a defect in dopamine biosynthesis. However, augmentation of gustatory plasticity was observed when bas-1 and cat-2 mutants were maintained on a growth medium containing nicotine along with dopamine, suggesting that dopamine signaling is involved in the augmentation of gustatory plasticity due to chronic nicotine exposure.

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Section: Involvement Of Dopamine Signaling Pathway In the Effects Of supporting

confidence: 59%

“…The chemotactic response of lev-1 and unc-29 mutants, which have a deficit in non-alpha subunits of nAChR, 31) to NaCl was examined to confirm whether nicotine affects the augmentation of gustatory plasticity via nAChR (Fig. 4).…”

Section: Effect Of Nachr On Augmentation Of Gustatory Plasticitymentioning

confidence: 99%

Chronic nicotine exposure augments gustatory plasticity inCaenorhabditis elegans:involvement of dopamine signaling

Matsuura

Urushihata

2015

Bioscience, Biotechnology, and Biochemistry

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“…By screening for mutant animals that survive exposure to levamisole, mutations in 5 genes encoding AChR subunits were found to confer partial or complete insensitivity to levamisole (4). These include 2 non-␣-subunits (LEV-1 and UNC-29) and 3 ␣-subunits (LEV-8, UNC-38, UNC-63) as defined by the presence of a vicinal dicysteine in the primary sequence (6)(7)(8). Consistently, electrophysiological analysis demonstrated a drastic reduction of levamisole-elicited currents in the muscle cells of these mutants.…”

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confidence: 65%

Eight genes are required for functional reconstitution of the Caenorhabditis elegans levamisole-sensitive acetylcholine receptor

Boulin

Gielen

Richmond

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

178

311

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Levamisole-sensitive acetylcholine receptors (L-AChRs) are ligandgated ion channels that mediate excitatory neurotransmission at the neuromuscular junctions of nematodes. They constitute a major drug target for anthelminthic treatments because they can be activated by nematode-specific cholinergic agonists such as levamisole. Genetic screens conducted in Caenorhabditis elegans for resistance to levamisole toxicity identified genes that are indispensable for the biosynthesis of L-AChRs. These include 5 genes encoding distinct AChR subunits and 3 genes coding for ancillary proteins involved in assembly and trafficking of the receptors. Despite extensive analysis of L-AChRs in vivo, pharmacological and biophysical characterization of these receptors has been greatly hampered by the absence of a heterologous expression system. Using Xenopus laevis oocytes, we were able to reconstitute functional L-AChRs by coexpressing the 5 distinct receptor subunits and the 3 ancillary proteins. Strikingly, this system recapitulates the genetic requirements for receptor expression in vivo because omission of any of these 8 genes dramatically impairs L-AChR expression. We demonstrate that 3 ␣-and 2 non-␣-subunits assemble into the same receptor. Pharmacological analysis reveals that the prototypical cholinergic agonist nicotine is unable to activate L-AChRs but rather acts as a potent allosteric inhibitor. These results emphasize the role of ancillary proteins for efficient expression of recombinant neurotransmitter receptors and open the way for in vitro screening of novel anthelminthic agents.anthelminthic drug ͉ recombinant receptor expression

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“…L-AChRs are heteropentameric receptors that can be activated by the nematode-specific cholinergic agonist levamisole. Levamisole causes hypercontraction of C. elegans body-wall muscles (BWMs) and death of WT worms at high concentrations (31,32). Genetic screens for resistance to levamisole have identified the structural subunits of the receptor, including three α subunits (LEV-8, UNC-38, and UNC-63) and two non-α subunits (LEV-1 and UNC-29).…”

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confidence: 99%

Biosynthesis of ionotropic acetylcholine receptors requires the evolutionarily conserved ER membrane complex

Richard

Boulin

Robert

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

110

146

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The number of nicotinic acetylcholine receptors (AChRs) present in the plasma membrane of muscle and neuronal cells is limited by the assembly of individual subunits into mature pentameric receptors. This process is usually inefficient, and a large number of the synthesized subunits are degraded by endoplasmic reticulum (ER)-associated degradation. To identify cellular factors required for the synthesis of AChRs, we performed a genetic screen in the nematode Caenorhabditis elegans for mutants with decreased sensitivity to the cholinergic agonist levamisole. We isolated a partial loss-of-function allele of ER membrane protein complex-6 (emc-6), a previously uncharacterized gene in C. elegans. emc-6 encodes an evolutionarily conserved 111-aa protein with two predicted transmembrane domains. EMC-6 is ubiquitously expressed and localizes to the ER. Partial inhibition of EMC-6 caused decreased expression of heteromeric levamisole-sensitive AChRs by destabilizing unassembled subunits in the ER. Inhibition of emc-6 also reduced the expression of homomeric nicotine-sensitive AChRs and GABA A receptors in C. elegans muscle cells. emc-6 is orthologous to the yeast and human EMC6 genes that code for a component of the recently identified ER membrane complex (EMC). Our data suggest this complex is required for protein folding and is connected to ER-associated degradation. We demonstrated that inactivation of additional EMC members in C. elegans also impaired AChR synthesis and induced the unfolded protein response. These results suggest that the EMC is a component of the ER folding machinery. AChRs might provide a valuable proxy to decipher the function of the EMC further.

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Caenorhabditis elegansLevamisole Resistance Geneslev-1,unc-29, andunc-38Encode Functional Nicotinic Acetylcholine Receptor Subunits

Cited by 309 publications

References 94 publications

Chronic nicotine exposure augments gustatory plasticity inCaenorhabditis elegans:involvement of dopamine signaling

Chronic nicotine exposure augments gustatory plasticity inCaenorhabditis elegans:involvement of dopamine signaling

Eight genes are required for functional reconstitution of the Caenorhabditis elegans levamisole-sensitive acetylcholine receptor

Biosynthesis of ionotropic acetylcholine receptors requires the evolutionarily conserved ER membrane complex

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