Mechanism of magnesium activation of calcium-activated potassium channels

Jingyi Shi, Gayathri Krishnamoorthy, Yanwu Yang, Lei Hu, Neha Chaturvedi, Dina Harilal, Jun Qin, Jianmin Cui

Research output: Contribution to journalArticlepeer-review

179 Scopus citations

Abstract

Large-conductance (BK type) Ca2+-dependent K+ channels are essential for modulating muscle contraction and neuronal activities such as synaptic transmission and hearing1-5. 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 helix12-15-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.

Original languageEnglish
Pages (from-to)876-880
Number of pages5
JournalNature
Volume418
Issue number6900
DOIs
StatePublished - Aug 22 2002

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