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BIOLOGICAL SCIENCES / NEUROSCIENCE
Mg²⁺ mediates interaction between the voltage sensor and cytosolic domain to activate BK channels

Huanghe Yang, Lei Hu, Jingyi Shi, Kelli Delaloye, Frank T. Horrigan, and Jianmin Cui^,

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

Edited by Ramón Latorre, Centro de Estudios Científicos, Valdivia, Chile, and approved September 25, 2007 (received for review June 22, 2007)

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.

electrostatic interaction | interdomain interaction | magnesium | Ca²⁺-activated K⁺ channel | metal ion regulation

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

^¶ Horrigan FT (2005) Biophys J 88:100A (abstr).

To whom correspondence should be addressed. E-mail: jcui{at}biomed.wustl.edu

© 2007 by The National Academy of Sciences of the USA

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