Subunit-specific effect of the voltage sensor domain on Ca2+ sensitivity of BK channels.
Large conductance Ca(2+)- and voltage-activated K(+) (BK) channels, composed of pore-forming alpha-subunits and auxiliary beta-subunits, play important roles in diverse physiological processes. The differences in BK channel phenotypes are primarily due to the tissue-specific expression of beta-subunits (beta1-beta4) that modulate channel function differently. Yet, the molecular basis of the subunit-specific regulation is not clear. In our study, we demonstrate that perturbation of the voltage sensor in BK channels by mutations selectively disrupts the ability of the beta1-subunit--but not that of the beta2-subunit--to enhance apparent Ca(2+) sensitivity. These mutations change the number of equivalent gating charges, the voltage dependence of voltage sensor movements, the open-close equilibrium of the channel, and the allosteric coupling between voltage sensor movements and channel opening to various degrees, indicating that they alter the conformation and movements of the voltage sensor and the activation gate. Similarly, the ability of the beta1-subunit to enhance apparent Ca(2+) sensitivity is diminished to various degrees, correlating quantitatively with the shift of voltage dependence of voltage sensor movements. In contrast, none of these mutations significantly reduces the ability of the beta2-subunit to enhance Ca(2+) sensitivity. These results suggest that the beta1-subunit enhances Ca(2+) sensitivity by altering the conformation and movements of the voltage sensor, whereas the similar function of the beta2-subunit is governed by a distinct mechanism.
Yang
Huanghe
H
Department of Biomedical Engineering and Cardiac Bioelectricity and Arrhythmia Center, Washington University, St. Louis, Missouri 63130, USA.
Zhang
Guohui
G
Shi
Jingyi
J
Lee
Urvi S
US
Delaloye
Kelli
K
Cui
Jianmin
J
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D015640:Ion Channel Gating / Q000502:physiology*; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000502:physiology*; D008565:Membrane Proteins / Q000378:metabolism*; D009865:Oocytes / Q000378:metabolism*; D021122:Protein Subunits; D013329:Structure-Activity Relationship; D014982:Xenopus laevis
D051036:Large-Conductance Calcium-Activated Potassium Channels; D008565:Membrane Proteins; D021122:Protein Subunits; D002118:Calcium