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