RRC ID 45743
著者 Hawkins EG, Martin I, Kondo LM, Judy ME, Brings VE, Chan CL, Blackwell GG, Bettinger JC, Davies AG.
タイトル A novel cholinergic action of alcohol and the development of tolerance to that effect in Caenorhabditis elegans.
ジャーナル Genetics
Abstract 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 ethanol-induced 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 α-subunit. We performed a forward genetic screen and identified eg200, a mutation that affects a conserved glycine in EAT-6, the α-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 α-subunit-containing nAChR is involved in ethanol-induced excitation and that tolerance to this ethanol effect is modulated by Na(+)/K(+) ATPase function.
巻・号 199(1)
ページ 135-49
公開日 2015-1-1
DOI 10.1534/genetics.114.171884
PII genetics.114.171884
PMID 25342716
PMC PMC4286678
MeSH Animals Caenorhabditis elegans / drug effects Caenorhabditis elegans / genetics* Caenorhabditis elegans / metabolism Caenorhabditis elegans / physiology Caenorhabditis elegans Proteins / genetics Caenorhabditis elegans Proteins / metabolism* Drug Tolerance* Ethanol / pharmacology* Membrane Proteins / genetics Membrane Proteins / metabolism* Muscle Contraction Mutation Protein Subunits / genetics Protein Subunits / metabolism Receptors, Nicotinic / genetics Receptors, Nicotinic / metabolism* Sodium-Potassium-Exchanging ATPase / genetics Sodium-Potassium-Exchanging ATPase / metabolism* Vesicular Acetylcholine Transport Proteins / genetics Vesicular Acetylcholine Transport Proteins / metabolism
IF 4.015
引用数 4
WOS 分野 GENETICS & HEREDITY
リソース情報
線虫 tm1406 tm1165