An epilepsy/dyskinesia-associated mutation enhances BK channel activation by potentiating Ca2+ sensing.
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.
Yang
Junqiu
J
Cardiac Bioelectricity and Arrhythmia Center, Washington University, St Louis, MO 63130, USA.
Krishnamoorthy
Gayathri
G
Saxena
Akansha
A
Zhang
Guohui
G
Shi
Jingyi
J
Yang
Huanghe
H
Delaloye
Kelli
K
Sept
David
D
Cui
Jianmin
J
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
D051036:Large-Conductance Calcium-Activated Potassium Channels; D009124:Muscle Proteins; C495444:PNKD protein, human; D001224:Aspartic Acid; D002118:Calcium; D005998:Glycine