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PNAS 105 (8): 3140-3144

Copyright © 2008 by the National Academy of Sciences.


BIOLOGICAL SCIENCES / PHYSIOLOGY

Acid-sensing ion channels interact with and inhibit BK K+ channels

Elena Yermolaieva Petroff*, Margaret P. Price*, Vladislav Snitsarev*, Huiyu Gong*, Victoria Korovkina{dagger}, Francois M. Abboud*,{dagger}, and Michael J. Welsh*,{dagger},{ddagger},§

Departments of *Internal Medicine and {dagger}Molecular Physiology and Biophysics and {ddagger}Howard Hughes Medical Institute, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242

Contributed by Michael J. Welsh, December 27, 2007

Received for publication December 4, 2007.

Abstract: Acid-sensing ion channels (ASICs) are neuronal non-voltage-gated cation channels that are activated when extracellular pH falls. They contribute to sensory function and nociception in the peripheral nervous system, and in the brain they contribute to synaptic plasticity and fear responses. Some of the physiologic consequences of disrupting ASIC genes in mice suggested that ASIC channels might modulate neuronal function by mechanisms in addition to their H+-evoked opening. Within ASIC channel's large extracellular domain, we identified sequence resembling that in scorpion toxins that inhibit K+ channels. Therefore, we tested the hypothesis that ASIC channels might inhibit K+ channel function by coexpressing ASIC1a and the high-conductance Ca2+- and voltage-activated K+ (BK) channel. We found that ASIC1a associated with BK channels and inhibited their current. Reducing extracellular pH disrupted the association and relieved the inhibition. BK channels, in turn, altered the kinetics of ASIC1a current. In addition to BK, ASIC1a inhibited voltage-gated Kv1.3 channels. Other ASIC channels also inhibited BK, although acidosis-dependent relief of inhibition varied. These results reveal a mechanism of ion channel interaction and reciprocal regulation. Finding that a reduced pH activated ASIC1a and relieved BK inhibition suggests that extracellular protons may enhance the activity of channels with opposing effects on membrane voltage. The wide and varied expression patterns of ASICs, BK, and related K+ channels suggest broad opportunities for this signaling system to alter neuronal function.


Freely available online through the PNAS open access option.

Author contributions: E.Y.P., M.P.P., V.S., F.M.A., and M.J.W. designed research; E.Y.P., M.P.P., V.S., and H.G. performed research; E.Y.P., M.P.P., H.G., and V.K. contributed new reagents/analytic tools; E.Y.P., M.P.P., V.S., F.M.A., and M.J.W. analyzed data; and E.Y.P., M.P.P., F.M.A., and M.J.W. wrote the paper.

The authors declare no conflict of interest.

This article contains supporting information online at www.pnas.org/cgi/content/full/0712280105/DC1.

§To whom correspondence should be addressed. E-mail: michael-welsh{at}uiowa.edu

© 2008 by The National Academy of Sciences of the USA


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