Neuron
Volume 66, Issue 6, 24 June 2010, Pages 871-883
Journal home page for Neuron

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

https://doi.org/10.1016/j.neuron.2010.05.009Get rights and content
Under an Elsevier user license
open archive

Summary

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.

Highlights

► The two Ca2+-activation pathways in BK channels are dissected ► The AC region is identified as a structural component of one of the pathways ► Protein dynamics plays an important role in the AC region pathway ► The disease-associated mutation alters channel dynamics to enhance Ca2+ sensing

MOLNEURO
PROTEINS
HUMDISEASE

Cited by (0)

6

Present address: Department of Biomedical Engineering and Center for Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA

7

These authors contributed equally to this work