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The Journal of Neuroscience, November 15, 1999, 19(22):9831-9840

Block of an ether-a-go-go-Like K+ Channel by Imipramine Rescues egl-2 Excitation Defects in Caenorhabditis elegans

David Weinshenker1, 2, Aguan Wei3, Lawrence Salkoff3, 4, and James H. Thomas1

1 Department of Genetics, and 2 Howard Hughes Medical Institute and Department of Biochemistry, University of Washington, Seattle, Washington 98195, and 3 Departments of Anatomy and Neurobiology and 4 Genetics, Washington University School of Medicine, St. Louis, Missouri 63110

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.

Key words: eag; K+ channel; tricyclic; antidepressant; imipramine; Caenorhabditis elegans; egl-2

Copyright © 1999 Society for Neuroscience  0270-6474/99/19229831-10$05.00/0


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