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 () and Jianmin Cui ()
Additional contact information
Guohui Zhang: Washington University
Xianjin Xu: University of Missouri – Columbia
Zhiguang Jia: University of Massachusetts
Yanyan Geng: University of Miami Miller School of Medicine
Hongwu Liang: Washington University
Jingyi Shi: Washington University
Martina Marras: Washington University
Carlota Abella: Washington University
Karl L. Magleby: University of Miami Miller School of Medicine
Jonathan R. Silva: Washington University
Jianhan Chen: University of Massachusetts
Xiaoqin Zou: University of Missouri – Columbia
Jianmin Cui: Washington University

Nature Communications, 2022, vol. 13, issue 1, 1-13

Abstract: 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.

Date: 2022
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-022-34359-6 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34359-6

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-022-34359-6

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().