期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：25
DOI：10.1073/pnas.2204620119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
BK channel voltage sensitivity is paramount for the physiology of excitable and nonexcitable tissues. Although the structure of the voltage sensor domain and number of charged residues in the S4 of BK is like that of Kv channels, BK voltage dependence is much weaker. Here, using gating current measurements and microsecond molecular simulations, we show that two S4 charges (R210 and R213) are the voltage-sensing particles. These residues undergo a small upward rotameric displacement in a septum devoid of water with only slight movement of S4 during activation. These findings explain the weak voltage dependence in BK and show that the mechanism of voltage sensing in BK channels is altogether different from that of Kv channels.
In neurosecretion, allosteric communication between voltage sensors and Ca
2+ binding in BK channels is crucially involved in damping excitatory stimuli. Nevertheless, the voltage-sensing mechanism of BK channels is still under debate. Here, based on gating current measurements, we demonstrate that two arginines in the transmembrane segment S4 (R210 and R213) function as the BK gating charges. Significantly, the energy landscape of the gating particles is electrostatically tuned by a network of salt bridges contained in the voltage sensor domain (VSD). Molecular dynamics simulations and proton transport experiments in the hyperpolarization-activated R210H mutant suggest that the electric field drops off within a narrow septum whose boundaries are defined by the gating charges. Unlike Kv channels, the charge movement in BK appears to be limited to a small displacement of the guanidinium moieties of R210 and R213, without significant movement of the S4.
