title: Distinct molecular targets including SLO-1 and gap junctions are engaged across a continuum of ethanol concentrations in Caenorhabditis elegans.
abstract: Ethanol (alcohol) interacts with diverse molecular effectors across a range of concentrations in the brain, eliciting intoxication through to sedation. Invertebrate models including the nematode worm Caenorhabditis elegans have been deployed for molecular genetic studies to inform on key components of these alcohol signaling pathways. C. elegans studies have typically employed external dosing with high (>250 mM) ethanol concentrations: A careful analysis of responses to low concentrations is lacking. Using the C. elegans pharyngeal system as a paradigm, we report a previously uncharacterized continuum of cellular and behavioral responses to ethanol from low (10 mM) to high (300 mM) concentrations. The complexity of these responses indicates that the pleiotropic action of ethanol observed in mammalian brain is conserved in this invertebrate model. We investigated two candidate ethanol effectors, the calcium-activated K(+) channel SLO-1 and gap junctions, and show that they contribute to, but are not sole determinants of, the low- and high-concentration effects, respectively. Notably, this study shows cellular and whole organismal behavioral responses to ethanol in C. elegans that directly equate to intoxicating through to supralethal blood alcohol concentrations in humans and provides an important benchmark for interpretation of paradigms that seek to inform on human alcohol use disorders.
authors.affiliation: 1Current address: Institute of Digital Healthcare, Warwick Manufacturing Group, University of Warwick, Coventry CV4 7AL, UK.
authors.forename: James
authors.initials: J
authors.lastname: Dillon
authors.forename: Ioannis
authors.initials: I
authors.lastname: Andrianakis
authors.forename: Richard
authors.initials: R
authors.lastname: Mould
authors.forename: Ben
authors.initials: B
authors.lastname: Ient
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.forename: Christopher
authors.initials: C
authors.lastname: James
authors.forename: Vincent
authors.initials: V
authors.lastname: O'Connor
authors.forename: Lindy
authors.initials: L
authors.lastname: Holden-Dye
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D017173:Caenorhabditis elegans / Q000187:drug effects* / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000494:pharmacology*; D005247:Feeding Behavior / Q000187:drug effects; D017629:Gap Junctions / Q000502:physiology*; D005786:Gene Expression Regulation; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000235:genetics / Q000378:metabolism*; D032342:Muscle Cells / Q000187:drug effects
chemical_list: D029742:Caenorhabditis elegans Proteins; D051036:Large-Conductance Calcium-Activated Potassium Channels; C494845:slo-1 protein, C elegans; D000431:Ethanol
keywords: alcohol; anesthesia; calcium-activated K+ channel; electrophysiology; intoxication; pharynx