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PNAS 103 (8): 2886-2891

Copyright © 2006 by the National Academy of Sciences.


BIOLOGICAL SCIENCES / NEUROSCIENCE

A voltage-driven switch for ion-independent signaling by ether-à-go-go K+ channels

Andrew P. Hegle, Daniel D. Marble, and Gisela F. Wilson*

Department of Molecular, Cellular, and Developmental Biology, University of Michigan, 830 North University Avenue, Ann Arbor, MI 48109-1048

Edited by Richard L. Huganir, Johns Hopkins University School of Medicine, Baltimore, MD, and approved December 23, 2005

Received for publication July 13, 2005.

Abstract: Voltage-gated channels maintain cellular resting potentials and generate neuronal action potentials by regulating ion flux. Here, we show that Ether-à-go-go (EAG) K+ channels also regulate intracellular signaling pathways by a mechanism that is independent of ion flux and depends on the position of the voltage sensor. Regulation of intracellular signaling was initially inferred from changes in proliferation. Specifically, transfection of NIH 3T3 fibroblasts or C2C12 myoblasts with either wild-type or nonconducting (F456A) eag resulted in dramatic increases in cell density and BrdUrd incorporation over vector- and Shaker-transfected controls. The effect of EAG was independent of serum and unaffected by changes in extracellular calcium. Inhibitors of p38 mitogen-activated protein (MAP) kinases, but not p44/42 MAP kinases (extracellular signal-regulated kinases), blocked the proliferation induced by nonconducting EAG in serum-free media, and EAG increased p38 MAP kinase activity. Importantly, mutations that increased the proportion of channels in the open state inhibited EAG-induced proliferation, and this effect could not be explained by changes in the surface expression of EAG. These results indicate that channel conformation is a switch for the signaling activity of EAG and suggest an alternative mechanism for linking channel activity to the activity of intracellular messengers, a role that previously has been ascribed only to channels that regulate calcium influx.

Key Words: intracellular messenger • mitogen-activated protein kinase • neuromodulation • proliferation • gating


Author contributions: A.P.H. and G.F.W. designed research; A.P.H., D.D.M., and G.F.W. performed research; A.P.H. and G.F.W. analyzed data; and A.P.H. and G.F.W. wrote the paper.

Conflict of interest statement: No conflicts declared.

This paper was submitted directly (Track II) to the PNAS office.

*To whom correspondence should be addressed. E-mail: wilsongf{at}umich.edu

© 2006 by The National Academy of Sciences of the USA


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