Coupling of Ca2+and voltage activation in BK channels through the aB helix/voltage sensor interface

Yanyan Geng, Zengqin Deng, Guohui Zhang, Gonzalo Budelli, Alice Butler, Peng Yuan, Jianmin Cui, Lawrence Salkoff, Karl L. Magleby

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Large-conductance Ca2+and voltage-activated K+ (BK) channels control membrane excitability in many cell types. BK channels are tetrameric. Each subunit is composed of a voltage sensor domain (VSD), a central pore-gate domain, and a large cytoplasmic domain (CTD) that contains the Ca2+sensors. While it is known that BK channels are activated by voltage and Ca2+, and that voltage and Ca2+activations interact, less is known about the mechanisms involved. We explore here these mechanisms by examining the gating contribution of an interface formed between the VSDs and the αB helices located at the top of the CTDs. Proline mutations in the αB helix greatly decreased voltage activation while having negligible effects on gating currents. Analysis with the Horrigan, Cui, and Aldrich model indicated a decreased coupling between voltage sensors and pore gate. Proline mutations decreased Ca2+activation for both Ca2+bowl and RCK1 Ca2+sites, suggesting that both high-affinity Ca2+sites transduce their effect, at least in part, through the aB helix. Mg2+ activation also decreased. The crystal structure of the CTD with proline mutation L390P showed a flattening of the first helical turn in the αB helix compared to wild type, without other notable differences in the CTD, indicating that structural changes from the mutation were confined to the aB helix. These findings indicate that an intact αB helix/VSD interface is required for effective coupling of Ca2+binding and voltage depolarization to pore opening and that shared Ca2+and voltage transduction pathways involving the aB helix may be involved.

Original languageEnglish
Pages (from-to)14512-14521
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number25
DOIs
StatePublished - Jun 23 2020

Keywords

  • Allosteric coupling
  • BK channel
  • Ca-activated Kchannel
  • Patch clamp
  • Slo1 channel

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