The Journal of General Physiology
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Published online December 31, 2007
doi:10.1085/jgp.200709877
The Journal of General Physiology, Vol. 131, No. 1, 13-32
The Rockefeller University Press, 0022-1295 $30.00
© 2007 Horrigan et al.
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ARTICLE

 Mg2+ Enhances Voltage Sensor/Gate Coupling in BK Channels



Frank T. Horrigan and Zhongming Ma

Department of Physiology, University of Pennsylvania School of Medicine Philadelphia, PA 19104

Correspondence to Frank T. Horrigan: horrigan{at}mail.med.upenn.edu

BK (Slo1) potassium channels are activated by millimolar intracellular Mg2+ as well as micromolar Ca2+ and membrane depolarization. Mg2+ and Ca2+ act in an approximately additive manner at different binding sites to shift the conductance–voltage (GK-V) relation, suggesting that these ligands might work through functionally similar but independent mechanisms. However, we find that the mechanism of Mg2+ action is highly dependent on voltage sensor activation and therefore differs fundamentally from that of Ca2+. Evidence that Ca2+ acts independently of voltage sensor activation includes an ability to increase open probability (PO) at extreme negative voltages where voltage sensors are in the resting state; 2 µM Ca2+ increases PO more than 15-fold at –120 mV. However 10 mM Mg2+, which has an effect on the GK-V relation similar to 2 µM Ca2+, has no detectable effect on PO when voltage sensors are in the resting state. Gating currents are only slightly altered by Mg2+ when channels are closed, indicating that Mg2+ does not act merely to promote voltage sensor activation. Indeed, channel opening is facilitated in a voltage-independent manner by Mg2+ in a mutant (R210C) whose voltage sensors are constitutively activated. Thus, 10 mM Mg2+ increases PO only when voltage sensors are activated, effectively strengthening the allosteric coupling of voltage sensor activation to channel opening. Increasing Mg2+ from 10 to 100 mM, to occupy very low affinity binding sites, has additional effects on gating that more closely resemble those of Ca2+. The effects of Mg2+ on steady-state activation and IK kinetics are discussed in terms of an allosteric gating scheme and the state-dependent interactions between Mg2+ and voltage sensor that may underlie this mechanism.

Abbreviations used in this paper: Kv, voltage-gated K+; RCK, regulator of K+ conductance.


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Related Article

Mg2+-dependent Regulation of BK Channels: Importance of Electrostatics
Christopher J. Lingle
J. Gen. Physiol. 2007 131: 5-11. [Full Text] [PDF]





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