title: An epilepsy/dyskinesia-associated mutation enhances BK channel activation by potentiating Ca2+ sensing.
abstract: 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.
authors.affiliation: Cardiac Bioelectricity and Arrhythmia Center, Washington University, St Louis, MO 63130, USA.
authors.forename: Junqiu
authors.initials: J
authors.lastname: Yang
authors.forename: Gayathri
authors.initials: G
authors.lastname: Krishnamoorthy
authors.forename: Akansha
authors.initials: A
authors.lastname: Saxena
authors.forename: Guohui
authors.initials: G
authors.lastname: Zhang
authors.forename: Jingyi
authors.initials: J
authors.lastname: Shi
authors.forename: Huanghe
authors.initials: H
authors.lastname: Yang
authors.forename: Kelli
authors.initials: K
authors.lastname: Delaloye
authors.forename: David
authors.initials: D
authors.lastname: Sept
authors.forename: Jianmin
authors.initials: J
authors.lastname: Cui
mesh_terms: D000494:Allosteric Regulation / Q000235:genetics; D000818:Animals; D001224:Aspartic Acid / Q000235:genetics; D002118:Calcium / Q000378:metabolism* / Q000494:pharmacology; D003198:Computer Simulation; D005998:Glycine / Q000235:genetics; D015640:Ion Channel Gating / Q000187:drug effects / Q000235:genetics; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000235:genetics / Q000378:metabolism*; D007814:Larva; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D008958:Models, Molecular; D015233:Models, Statistical; D009124:Muscle Proteins / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D017711:Nonlinear Dynamics; D009865:Oocytes; D018408:Patch-Clamp Techniques; D025341:Principal Component Analysis; D016415:Sequence Alignment; D014981:Xenopus
chemical_list: D051036:Large-Conductance Calcium-Activated Potassium Channels; D009124:Muscle Proteins; C495444:PNKD protein, human; D001224:Aspartic Acid; D002118:Calcium; D005998:Glycine