A Neuronal Acetylcholine Receptor Regulates the Balance of Muscle Excitation and Inhibition in Caenorhabditis elegans

Jospin, Maëlle; Qi, Yingchuan; Stawicki, Tamara M.; Boulin, Thomas; Schuske, Kim; Horvitz, H. Robert; Bessereau, Jean-Louis; Jørgensen, Erik M.; Jin, Yishi

doi:10.1371/journal.pbio.1000265

Cited by 117 publications

(194 citation statements)

References 47 publications

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“…RIC-3 was identified in a suppressor screen of neuronal degeneration caused by a gain-of-function mutation in the C. elegans AChR composed of DEG-3 and DES-2 subunits (35). RIC-3 is a small integral membrane protein located in the ER that is required for the assembly of at least five distinct AChR receptors in C. elegans, including L-AChRs and N-AChRs (35)(36)(37). RIC-3 is conserved in flies and mammals, and it can either promote or inhibit the expression of AChRs and 5-HT3 receptors in heterologous systems (reviewed in ref.…”

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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.

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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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mentioning

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.

Self Cite

105

146

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“…As ACh receptors regulate the balance of muscle excitation and inhibition (Jospin et al, 2009;Barbagallo et al, 2010), and ACh impacts stamina and action potential of muscles (Lund et al, 2010), ACh receptor mutations lead to motor neuron degeneration. Indeed, ageing reduces ACh release and diminishes motor performance (Freeman and Gibson, 1988).…”

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confidence: 99%

Human adipose tissue‐derived mesenchymal stem cells improve cognitive function and physical activity in ageing mice

Park

Yang

Bae

et al. 2013

J of Neuroscience Research

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Brain ageing leads to atrophy and degeneration of the cholinergic nervous system, resulting in profound neurobehavioral and cognitive dysfunction from decreased acetylcholine biosynthesis and reduced secretion of growth and neurotrophic factors. Human adipose tissue-derived mesenchymal stem cells (ADMSCs) were intravenously (1 3 10 6 cells) or intracerebroventricularly (4 3 10 5 cells) transplanted into the brains of 18-month-old mice once or four times at 2-week intervals. Transplantation of ADMSCs improved both locomotor activity and cognitive function in the aged animals, in parallel with recovery of acetylcholine levels in brain tissues. Transplanted cells differentiated into neurons and, in part, into astrocytes and produced choline acetyltransferase proteins. Transplantation of ADMSCs restored microtubule-associated protein 2 in brain tissue and enhanced Trk B expression and the concentrations of brain-derived neurotrophic factor and nerve growth factor. These results indicate that human ADMSCs differentiate into neural cells in the brain microenvironment and can restore physical and cognitive functions of aged mice not only by increasing acetylcholine synthesis but also by restoring neuronal integrity that may be mediated by growth/neurotrophic factors. V V C 2013 Wiley Periodicals, Inc.

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“…We tested the only additional receptor currently known to include the UNC-63 subunit, the neuronal ACR-2 receptor (Jospin et al 2009;Petrash et al 2013), and found that loss of that receptor, through loss of function in the acr-2 gene, did not alter sensitivity to EHC. These results suggest that UNC-63 is likely to act in an as yet unidentified receptor(s) to mediate EHC.…”

Section: Cholinergic Signalingmentioning

confidence: 99%

“…Instead, these data suggest the involvement of the UNC-63 subunit in a different receptor(s). One likely candidate was the neuronal ACR-2 receptor (ACR-2R), which has been shown to require UNC-63 and UNC-38 subunits (Jospin et al 2009) and is expressed in cholinergic motorneurons (Petrash et al 2013). Loss of function of the acr-2 gene eliminates the ACR-2R, so we tested acr-2(ok1887) for EHC, with the idea that if UNC-63 were acting in the ACR-2R to mediate EHC, then loss of ACR-2R should mimic the unc-63(lf) for this phenotype.…”

mentioning

confidence: 99%

“…Our finding that other subunits required for the levamisolesensitive nAChR (Fleming et al 1997;Culetto et al 2004) are not required for EHC suggests that UNC-63 is acting in a different receptor to mediate EHC. We tested the only additional receptor currently known to include the UNC-63 subunit, the neuronal ACR-2 receptor (Jospin et al 2009;Petrash et al 2013), and found that loss of that receptor, through loss of function in the acr-2 gene, did not alter sensitivity to EHC. These results suggest that UNC-63 is likely to act in an as yet unidentified receptor(s) to mediate EHC.…”

mentioning

confidence: 99%

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A Novel Cholinergic Action of Alcohol and the Development of Tolerance to That Effect inCaenorhabditis elegans

et al. 2014

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Understanding the genes and mechanisms involved in acute alcohol responses has the potential to allow us to predict an individual's predisposition to developing an alcohol use disorder. To better understand the molecular pathways involved in the activating effects of alcohol and the acute functional tolerance that can develop to such effects, we characterized a novel ethanolinduced hypercontraction response displayed by Caenorhabditis elegans. We compared body size of animals prior to and during ethanol treatment and showed that acute exposure to ethanol produced a concentration-dependent decrease in size followed by recovery to their untreated size by 40 min despite continuous treatment. An increase in cholinergic signaling, leading to muscle hypercontraction, is implicated in this effect because pretreatment with mecamylamine, a nicotinic acetylcholine receptor (nAChR) antagonist, blocked ethanol-induced hypercontraction, as did mutations causing defects in cholinergic signaling (cha-1 and unc-17). Analysis of mutations affecting specific subunits of nAChRs excluded a role for the ACR-2R, the ACR-16R, and the levamisole-sensitive AChR and indicated that this excitation effect is dependent on an uncharacterized nAChR that contains the UNC-63 a-subunit. We performed a forward genetic screen and identified eg200, a mutation that affects a conserved glycine in EAT-6, the a-subunit of the Na + /K + ATPase. The eat-6(eg200) mutant fails to develop tolerance to ethanol-induced hypercontraction and remains contracted for at least 3 hr of continuous ethanol exposure. These data suggest that cholinergic signaling through a specific a-subunit-containing nAChR is involved in ethanol-induced excitation and that tolerance to this ethanol effect is modulated by Na + /K + ATPase function.T HE abuse of alcohol is a cause of significant societal and health-related problems. Despite the common usage of this drug, the molecular underpinnings of alcohol's acute actions on the brain are poorly understood. Alcohol (ethanol) has biphasic behavioral effects in humans and other animals, acting as a stimulant at lower concentrations and as a depressant at higher concentrations. Understanding the molecular nature of these biphasic effects is made difficult by the fact that ethanol interacts with, and alters the function of, many proteins, including neurotransmitter receptors and ion channels (Harris et al. 2008;Spanagel 2009). A commonly suggested class of ethanol targets is ligand-gated ion channels (LGICs), which include NMDA glutamate receptors, and members of a subclass of LGICs, the Cys-loop superfamily, including GABA A , glycine, and nicotinic acetylcholine receptors (nAChRs) (Olsen et al. 2014). Effects on the GABA A and glutamate receptors are hypothesized to play a significant role in the depressant effects of ethanol (Harris et al. 2008). Locomotor activation by low to moderate concentrations of ethanol in rodents is thought to model the euphoric effects of ethanol in humans (Phillips and Shen 1996). Locomotor activat...

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A Neuronal Acetylcholine Receptor Regulates the Balance of Muscle Excitation and Inhibition in Caenorhabditis elegans

Abstract: The role of a heterotrimeric neuronal acetylcholine receptor in regulating a Caenorhabditis elegans locomotion circuit are revealed down to the level of identifying all five subunits involved.

Cited by 117 publications

References 47 publications

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

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

Human adipose tissue‐derived mesenchymal stem cells improve cognitive function and physical activity in ageing mice

A Novel Cholinergic Action of Alcohol and the Development of Tolerance to That Effect inCaenorhabditis elegans

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