Functional genomics of the nicotinic acetylcholine receptor gene family of the nematode, <i>Caenorhabditis elegans</i>

Jones, Andrew K.; Sattelle, David B.

doi:10.1002/bies.10377

Cited by 144 publications

(149 citation statements)

References 94 publications

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“…These nAchRs are discriminated from each other by their sensitivities to different Ach agonists: the levamisolesensitive receptor and nicotine-sensitive receptor. The levamisole receptor is thought to contain UNC-38/UNC-63 α subunits and UNC-29/LEV-1 non-α subunits (Culetto et al, 2004;Fleming et al, 1997;Jones and Sattelle, 2004;Richmond and Jorgensen, 1999), whereas the nicotine receptor contains ACR-16 α subunit (Francis et al, 2005). Recently, the transmembrane CUB/ LDL protein LEV-10 was found to regulate the clustering of levamisole-sensitive receptors at NMJs (Gally et al, 2004), and the receptor tyrosine kinase CAM-1 was required for the localization of the nicotine-sensitive ACR-16 receptor at postsynaptic sites (Francis et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Na+/K+ ATPase regulates the expression and localization of acetylcholine receptors in a pump activity-independent manner

Doi

Iwasaki

2008

Molecular and Cellular Neuroscience

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Na + /K + ATPase is a plasma membrane-localized sodium pump that maintains the ion gradients between the extracellular and intracellular environments, which in turn controls the cellular resting membrane potential. Recent evidence suggests that the pump is also localized at synapses and regulates synaptic efficacy. However, its precise function at the synapse is unknown. Here we show that two mutations in the α subunit of the eat-6 Na + /K + ATPase in Caenorhabditis elegans dramatically increase the sensitivity to acetylcholine (Ach) agonists and alter the localization of nicotinic Ach receptors at the neuromuscular junction (NMJ). These defects can be rescued by mutated EAT-6 proteins which lack its pump activity, suggesting the presence of a novel function for Ach signaling. The Na + /K + ATPase accumulates at postsynaptic sites and appears to surround Ach receptors to maintain rigid clusters at the NMJ. Our findings suggest a critical pump activityindependent, allele -specific role for Na + /K + ATPase on postsynaptic organization and synaptic efficacy.

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Section: Introductionmentioning

confidence: 99%

Na+/K+ ATPase regulates the expression and localization of acetylcholine receptors in a pump activity-independent manner

Doi

Iwasaki

2008

Molecular and Cellular Neuroscience

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“…Specifically, the nematode Caenorhabditis elegans is a powerful model organism with which to dissect AChR biosynthesis genetically. ACh is the main excitatory neurotransmitter in C. elegans, and at least 29 genes encode AChR subunits (29). Two types of ionotropic AChRs, heteromeric levamisole-sensitive AChRs (L-AChRs) and homomeric nicotine-sensitive AChRs (N-AChRs), are present at the neuromuscular junction (NMJ), the best-characterized cholinergic synapse in the worm (30).…”

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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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“…Acetylcholine is the main excitatory neurotransmitter in C. elegans, and Ͼ29 genes encoding AChR subunits are predicted from its genome sequence (5). Despite this complexity, genetic screens were able to identify the genes coding for the subunits of levamisole-sensitive AChRs (L-AChRs).…”

mentioning

confidence: 99%

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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Functional genomics of the nicotinic acetylcholine receptor gene family of the nematode, Caenorhabditis elegans

Cited by 144 publications

References 94 publications

Na+/K+ ATPase regulates the expression and localization of acetylcholine receptors in a pump activity-independent manner

Na+/K+ ATPase regulates the expression and localization of acetylcholine receptors in a pump activity-independent manner

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

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

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