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

Guohui Zhang, Xianjin Xu, Zhiguang Jia, Yanyan Geng, Hongwu Liang, Jingyi Shi, Martina Marras, Carlota Abella, Karl L. Magleby, Jonathan R. Silva, Jianhan Chen, Xiaoqin Zou, Jianmin Cui

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

BK type Ca2+-activated K+ channels activate in response to both voltage and Ca2+. The membrane-spanning voltage sensor domain (VSD) activation and Ca2+ binding to the cytosolic tail domain (CTD) open the pore across the membrane, but the mechanisms that couple VSD activation and Ca2+ 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 Ca2+ dependent activation mechanism. BC5 activates the channel in the absence of Ca2+ binding but Ca2+ binding inhibits BC5 effects. Thus, BC5 perturbs a pathway that couples Ca2+ 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 Ca2+ dependent activation and is an important site for allosteric agonists to modulate BK channel activation.

Original languageEnglish
Article number6784
JournalNature communications
Volume13
Issue number1
DOIs
StatePublished - Dec 2022

Fingerprint

Dive into the research topics of 'An allosteric modulator activates BK channels by perturbing coupling between Ca2+ binding and pore opening'. Together they form a unique fingerprint.

Cite this