title: Block of an ether-a-go-go-like K(+) channel by imipramine rescues egl-2 excitation defects in Caenorhabditis elegans.
abstract: K(+) channels are key regulators of cellular excitability. Mutations that activate K(+) channels can lower cellular excitability, whereas those that inhibit K(+) channels may increase excitability. We show that the Caenorhabditis elegans egl-2 gene encodes an eag K(+) channel and that a gain-of-function mutation in egl-2 blocks excitation in neurons and muscles by causing the channel to open at inappropriately negative voltages. Tricyclic antidepressants reverse egl-2(gf) mutant phenotypes, suggesting that EGL-2 is a tricyclic target. We verified this by showing that EGL-2 currents are inhibited by imipramine. Similar inhibition is observed with the mouse homolog MEAG, suggesting that inhibition of EAG-like channels may mediate some clinical side effects of this class of antidepressants.
authors.affiliation: Department of Genetics, University of Washington, Seattle, Washington 98195, USA.
authors.forename: D
authors.initials: D
authors.lastname: Weinshenker
authors.forename: A
authors.initials: A
authors.lastname: Wei
authors.forename: L
authors.initials: L
authors.lastname: Salkoff
authors.forename: J H
authors.initials: JH
authors.lastname: Thomas
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000502:physiology*; D002633:Chemotaxis; D051638:Ether-A-Go-Go Potassium Channels; D005020:Ethyl Methanesulfonate; D005260:Female; D005838:Genotype; D015801:Helminth Proteins / Q000235:genetics; D007099:Imipramine / Q000494:pharmacology*; D051379:Mice; D008969:Molecular Sequence Data; D009043:Motor Activity; D016296:Mutagenesis; D009474:Neurons / Q000502:physiology*; D010058:Oviposition; D010641:Phenotype; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000737:chemistry / Q000502:physiology*; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid
chemical_list: D051638:Ether-A-Go-Go Potassium Channels; D015801:Helminth Proteins; C496885:Kcnh1 protein, mouse; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D005020:Ethyl Methanesulfonate; D007099:Imipramine