Mg2+ mediates interaction between the voltage sensor and cytosolic domain to activate BK channels
- †Department of Biomedical Engineering and Cardiac Bioelectricity and Arrhythmia Center, Washington University, St. Louis, MO 63130; and
- ‡Department of Physiology, University of Pennsylvania, Philadelphia, PA 19104-6085
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Edited by Ramón Latorre, Centro de Estudios Científicos, Valdivia, Chile, and approved September 25, 2007 (received for review June 22, 2007)
Abstract
The voltage-sensor domain (VSD) of voltage-dependent ion channels and enzymes is critical for cellular responses to membrane potential. The VSD can also be regulated by interaction with intracellular proteins and ligands, but how this occurs is poorly understood. Here, we show that the VSD of the BK-type K+ channel is regulated by a state-dependent interaction with its own tethered cytosolic domain that depends on both intracellular Mg2+ and the open state of the channel pore. Mg2+ bound to the cytosolic RCK1 domain enhances VSD activation by electrostatic interaction with Arg-213 in transmembrane segment S4. Our results demonstrate that a cytosolic domain can come close enough to the VSD to regulate its activity electrostatically, thereby elucidating a mechanism of Mg2+-dependent activation in BK channels and suggesting a general pathway by which intracellular factors can modulate the function of voltage-dependent proteins.
Footnotes
- §To whom correspondence should be addressed. E-mail: jcui{at}biomed.wustl.edu
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Author contributions: H.Y. and L.H. contributed equally to this work; H.Y., L.H., and J.C. designed research; H.Y., L.H., J.S., and K.D. performed research; F.T.H. contributed new reagents/analytic tools; H.Y. and L.H. analyzed data; and H.Y., F.T.H., and J.C. wrote the paper.
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The authors declare no conflict of interest.
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This article is a PNAS Direct Submission.
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↵ ¶ Horrigan FT (2005) Biophys J 88:100A (abstr).
- Abbreviations:
- VSD,
- voltage-sensor domain;
- Kv,
- voltage-dependent K+;
- V1/2,
- voltage at half-maximum conductance;
- Vhc,
- voltage for half of the gating charge movements at the closed conformation of the channel;
- Ig,
- gating current;
- IgON,
- on Ig;
- IgOFF,
- off Ig;
- IK,
- K+ ionic current;
- [Mg2+]i,
- intracellular Mg2+ concentration;
- [K+]i,
- intracellular K+ concentration;
- Po,
- open probability;
- [Ca2+]i,
- intracellular Ca2+ concentration.
- © 2007 by The National Academy of Sciences of the USA
