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Mechanism of magnesium activation of calcium-activated potassium channels

Author

Listed:
  • Jingyi Shi

    (Case Western Reserve University)

  • Gayathri Krishnamoorthy

    (Case Western Reserve University)

  • Yanwu Yang

    (The Cleveland Clinic Foundation)

  • Lei Hu

    (Case Western Reserve University)

  • Neha Chaturvedi

    (Case Western Reserve University)

  • Dina Harilal

    (Case Western Reserve University)

  • Jun Qin

    (The Cleveland Clinic Foundation)

  • Jianmin Cui

    (Case Western Reserve University)

Abstract

Large-conductance (BK type) Ca2+-dependent K+ channels are essential for modulating muscle contraction and neuronal activities such as synaptic transmission and hearing1,2,3,4,5. BK channels are activated by membrane depolarization and intracellular Ca2+ and Mg2+ (refs 6–10). The energy provided by voltage, Ca2+ and Mg2+ binding are additive in activating the channel, suggesting that these signals open the activation gate through independent pathways9,11. Here we report a molecular investigation of a Mg2+-dependent activation mechanism. Using a combined site-directed mutagenesis and structural analysis, we demonstrate that a structurally new Mg2+-binding site in the RCK/Rossman fold domain—an intracellular structural motif that immediately follows the activation gate S6 helix12,13,14,15—is responsible for Mg2+-dependent activation. Mutations that impair or abolish Mg2+ sensitivity do not affect Ca2+ sensitivity, and vice versa. These results indicate distinct structural pathways for Mg2+- and Ca2+-dependent activation and suggest a possible mechanism for the coupling between Mg2+ binding and channel opening.

Suggested Citation

  • Jingyi Shi & Gayathri Krishnamoorthy & Yanwu Yang & Lei Hu & Neha Chaturvedi & Dina Harilal & Jun Qin & Jianmin Cui, 2002. "Mechanism of magnesium activation of calcium-activated potassium channels," Nature, Nature, vol. 418(6900), pages 876-880, August.
    • Handle: RePEc:nat:nature:v:418:y:2002:i:6900:d:10.1038_nature00941
    DOI: 10.1038/nature00941
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    Cited by:

    1. Yu-Li Ni & Ai-Seon Kuan & Tsung-Yu Chen, 2014. "Activation and Inhibition of TMEM16A Calcium-Activated Chloride Channels," PLOS ONE, Public Library of Science, vol. 9(1), pages 1-12, January.
    2. Guohui Zhang & Xianjin Xu & Zhiguang Jia & Yanyan Geng & Hongwu Liang & Jingyi Shi & Martina Marras & Carlota Abella & Karl L. Magleby & Jonathan R. Silva & Jianhan Chen & Xiaoqin Zou & Jianmin Cui, 2022. "An allosteric modulator activates BK channels by perturbing coupling between Ca2+ binding and pore opening," Nature Communications, Nature, vol. 13(1), pages 1-13, December.

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