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An epilepsy/dyskinesia-associated mutation enhances BK channel activation by potentiating Ca2+ sensing.

Publication ,  Journal Article
Yang, J; Krishnamoorthy, G; Saxena, A; Zhang, G; Shi, J; Yang, H; Delaloye, K; Sept, D; Cui, J
Published in: Neuron
June 24, 2010

Ca(2+)-activated BK channels modulate neuronal activities, including spike frequency adaptation and synaptic transmission. Previous studies found that Ca(2+)-binding sites and the activation gate are spatially separated in the channel protein, but the mechanism by which Ca(2+) 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 Ca(2+) binding and channel opening. The GEPD mutation inside the AC region increases BK channel activity by enhancing this allosteric coupling. We found that Ca(2+) 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 Ca(2+) binding to channel opening.

Duke Scholars

Published In

Neuron

DOI

EISSN

1097-4199

Publication Date

June 24, 2010

Volume

66

Issue

6

Start / End Page

871 / 883

Location

United States

Related Subject Headings

  • Xenopus
  • Sequence Alignment
  • Principal Component Analysis
  • Patch-Clamp Techniques
  • Oocytes
  • Nonlinear Dynamics
  • Neurology & Neurosurgery
  • Mutation
  • Muscle Proteins
  • Models, Statistical
 

Citation

APA
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ICMJE
MLA
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Yang, J., Krishnamoorthy, G., Saxena, A., Zhang, G., Shi, J., Yang, H., … Cui, J. (2010). An epilepsy/dyskinesia-associated mutation enhances BK channel activation by potentiating Ca2+ sensing. Neuron, 66(6), 871–883. https://doi.org/10.1016/j.neuron.2010.05.009
Yang, Junqiu, Gayathri Krishnamoorthy, Akansha Saxena, Guohui Zhang, Jingyi Shi, Huanghe Yang, Kelli Delaloye, David Sept, and Jianmin Cui. “An epilepsy/dyskinesia-associated mutation enhances BK channel activation by potentiating Ca2+ sensing.Neuron 66, no. 6 (June 24, 2010): 871–83. https://doi.org/10.1016/j.neuron.2010.05.009.
Yang J, Krishnamoorthy G, Saxena A, Zhang G, Shi J, Yang H, et al. An epilepsy/dyskinesia-associated mutation enhances BK channel activation by potentiating Ca2+ sensing. Neuron. 2010 Jun 24;66(6):871–83.
Yang, Junqiu, et al. “An epilepsy/dyskinesia-associated mutation enhances BK channel activation by potentiating Ca2+ sensing.Neuron, vol. 66, no. 6, June 2010, pp. 871–83. Pubmed, doi:10.1016/j.neuron.2010.05.009.
Yang J, Krishnamoorthy G, Saxena A, Zhang G, Shi J, Yang H, Delaloye K, Sept D, Cui J. An epilepsy/dyskinesia-associated mutation enhances BK channel activation by potentiating Ca2+ sensing. Neuron. 2010 Jun 24;66(6):871–883.
Journal cover image

Published In

Neuron

DOI

EISSN

1097-4199

Publication Date

June 24, 2010

Volume

66

Issue

6

Start / End Page

871 / 883

Location

United States

Related Subject Headings

  • Xenopus
  • Sequence Alignment
  • Principal Component Analysis
  • Patch-Clamp Techniques
  • Oocytes
  • Nonlinear Dynamics
  • Neurology & Neurosurgery
  • Mutation
  • Muscle Proteins
  • Models, Statistical