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

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.