An Epilepsy/Dyskinesia-Associated Mutation Enhances BK Channel Activation by Potentiating Ca2+ Sensing

Junqiu Yang, Gayathri Krishnamoorthy, Akansha Saxena, Guohui Zhang, Jingyi Shi, Huanghe Yang, Kelli Delaloye, David Sept, Jianmin Cui

Research output: Contribution to journalArticlepeer-review

91 Scopus citations

Abstract

Ca2+-activated BK channels modulate neuronal activities, including spike frequency adaptation and synaptic transmission. Previous studies found that Ca2+-binding sites and the activation gate are spatially separated in the channel protein, but the mechanism by which Ca2+ binding opens the gate over this distance remains unknown. By studying an Asp-to-Gly mutation (D434G) associated with human syndrome of generalized epilepsy and paroxysmal dyskinesia (GEPD), we show that a cytosolic motif immediately following the activation gate S6 helix, known as the AC region, mediates the allosteric coupling between Ca2+ binding and channel opening. The GEPD mutation inside the AC region increases BK channel activity by enhancing this allosteric coupling. We found that Ca2+ sensitivity is enhanced by increases in solution viscosity that reduce protein dynamics. The GEPD mutation alters such a response, suggesting that a less flexible AC region may be more effective in coupling Ca2+ binding to channel opening.

Original languageEnglish
Pages (from-to)871-883
Number of pages13
JournalNeuron
Volume66
Issue number6
DOIs
StatePublished - Jun 2010

Keywords

  • Humdisease
  • Molneuro
  • Proteins

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