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Activation of Slo1 BK channels by Mg2+ coordinated between the voltage sensor and RCK1 domains

Nature Structural & Molecular Biology volume 15, pages 1152–1159 (2008)Cite this article

Abstract

The voltage-sensor domain (VSD) and the ligand sensor (cytoplasmic domain) of BK channels synergistically control channel activities, thereby integrating electrical and chemical signals for cell function. Studies show that intracellular Mg2+ mediates the interaction between these sensory domains to activate the channel through an electrostatic interaction with the VSD. Here we report that Mg2+ binds to a site that consists of amino acid side chains from both the VSD (Asp99 and Asn172) and the cytoplasmic domain (Glu374 and Glu399). For each Mg2+ binding site, the residues in the VSD and those in the cytoplasmic domain come from neighboring subunits. These results suggest that the VSD and the cytoplasmic domains from different subunits may interact during channel gating, and the packing of VSD or the RCK1 domain to the pore in BK channels differ from that in Kv1.2 or MthK channels.

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Figure 1: Mg2+ coordinates in the cytoplasmic domain of the mouse Slo1 channel.
Figure 2: D99A abolishes Mg2+ sensitivity by preventing Mg2+ binding.
Figure 3: Asp99 is spatially close to the cytoplasmic part of the Mg2+ binding site.
Figure 4: The side chain carboxylate or carbonyl group of residue 99 is required for Mg2+ coordination.
Figure 5: Asn172 may contribute to Mg2+ coordination.
Figure 6: Asp99 and Glu374 in a Mg2+ binding site are not from the same subunit.
Figure 7: Asp99 and Asn172, and Glu374 and Glu399, may come from neighboring subunits to form a Mg2+ binding site.

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Acknowledgements

We thank L. Hu for calculations of Mg2+ sensitivity according to the model of the intersubunit Mg2+ binding site. We thank C. Lingle, L. Salkoff and L. Hu for critical discussion. The mouse Slo1 clone was provided by L. Salkoff (Washington University). F. Horrigan (Baylor College of Medicine) provided the Y163K mutant mouse Slo1 cDNA. This work was supported by the US National Institutes of Health Grant R01-HL70393 and the National Science Foundation of China Grant 30528011 (J.C.). J.C. is funded by the Spencer T. Olin Endowment.

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  1. Department of Biomedical Engineering, and Cardiac Bioelectricity and Arrhythmia Center, Washington University, 1 Brookings Drive, St. Louis, 63130, Missouri, USA

    Huanghe Yang, Jingyi Shi, Guohui Zhang, Junqiu Yang, Kelli Delaloye & Jianmin Cui

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Contributions

H.Y., J.S. and J.C. designed the research; H.Y., J.S., G.Z., J.Y. and K.D. performed the experiments; H.Y., G.Z. and J.Y. analyzed the data; H.Y. and J.C. wrote the paper.

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Correspondence to Jianmin Cui.

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Yang, H., Shi, J., Zhang, G. et al. Activation of Slo1 BK channels by Mg2+ coordinated between the voltage sensor and RCK1 domains. Nat Struct Mol Biol 15, 1152–1159 (2008). https://doi.org/10.1038/nsmb.1507

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