An allosteric modulator activates BK channels by perturbing coupling between Ca2+ binding and pore opening

• Published in: Nature communications Vol. 13; no. 1; pp. 1 - 13
• Main Authors: Zhang, Guohui, Xu, Xianjin, Jia, Zhiguang, Geng, Yanyan, Liang, Hongwu, Shi, Jingyi, Marras, Martina, Abella, Carlota, Magleby, Karl L., Silva, Jonathan R., Chen, Jianhan, Zou, Xiaoqin, Cui, Jianmin
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 09.11.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 119/118; 38/70; 631/1647/1453; 631/45/269; 631/57/2266; 631/57/2270/1140; 9/74; 9/97; Allosteric properties; Binding; Biochemistry; Calcium channels; Calcium channels (voltage-gated); Calcium ions; Channels; Domains; Electric potential; Humanities and Social Sciences; Ions; Membranes; multidisciplinary; Muscles; Mutagenesis; Potassium channels (calcium-gated); Reproducibility; Science; Science (multidisciplinary); Sensors; Voltage
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-34359-6

BK type Ca 2+ -activated K + channels activate in response to both voltage and Ca 2+ . The membrane-spanning voltage sensor domain (VSD) activation and Ca 2+ binding to the cytosolic tail domain (CTD) open the pore across the membrane, but the mechanisms that couple VSD activation and Ca 2+ binding to pore opening  are not clear. Here we show that a compound, BC5, identified from in silico screening, interacts with the CTD-VSD interface and specifically modulates the Ca 2+ dependent activation mechanism. BC5 activates the channel in the absence of Ca 2+ binding but Ca 2+ binding inhibits BC5 effects. Thus, BC5 perturbs a pathway that couples Ca 2+ binding to pore opening to allosterically affect both, which is further supported by atomistic simulations and mutagenesis. The results suggest that the CTD-VSD interaction makes a major contribution to the mechanism of Ca 2+ dependent activation and is an important site for allosteric agonists to modulate BK channel activation. Ca 2+ activated BK channels are important for neural and muscle function. Here authors use a compound, BC5, to show that the interface between the cytosolic and voltage sensing domains is a major allosteric pathway for Ca 2+ binding to open the channel.