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

doi:10.1038/s41467-022-34359-6

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

Nat Commun. 2022 Nov 9;13(1):6784. doi: 10.1038/s41467-022-34359-6.

Authors

Guohui Zhang^#¹, Xianjin Xu^#^{2

3

4

5}, Zhiguang Jia^#^{6

7}, Yanyan Geng⁸, Hongwu Liang¹, Jingyi Shi¹, Martina Marras¹, Carlota Abella¹, Karl L Magleby⁸, Jonathan R Silva⁹, Jianhan Chen^{10

11}, Xiaoqin Zou^{12

13

14

15}, Jianmin Cui¹⁶

Affiliations

¹ Department of Biomedical Engineering, Center for the Investigation of Membrane Excitability Disorders, Cardiac Bioelectricity and Arrhythmia Center, Washington University, St. Louis, MO, USA.
² Dalton Cardiovascular Research Center, University of Missouri - Columbia, Columbia, MO, USA.
³ Department of Physics and Astronomy, University of Missouri - Columbia, Columbia, MO, USA.
⁴ Department of Biochemistry, University of Missouri - Columbia, Columbia, MO, USA.
⁵ Institute for Data Science and Informatics, University of Missouri - Columbia, Columbia, MO, USA.
⁶ Department of Chemistry, University of Massachusetts, Amherst, MA, USA.
⁷ Department of Biochemistry and Molecular Biology, University of Massachusetts, Amherst, MA, USA.
⁸ Department of Physiology and Biophysics, University of Miami Miller School of Medicine, Miami, FL, USA.
⁹ Department of Biomedical Engineering, Center for the Investigation of Membrane Excitability Disorders, Cardiac Bioelectricity and Arrhythmia Center, Washington University, St. Louis, MO, USA. [email protected].
¹⁰ Department of Chemistry, University of Massachusetts, Amherst, MA, USA. [email protected].
¹¹ Department of Biochemistry and Molecular Biology, University of Massachusetts, Amherst, MA, USA. [email protected].
¹² Dalton Cardiovascular Research Center, University of Missouri - Columbia, Columbia, MO, USA. [email protected].
¹³ Department of Physics and Astronomy, University of Missouri - Columbia, Columbia, MO, USA. [email protected].
¹⁴ Department of Biochemistry, University of Missouri - Columbia, Columbia, MO, USA. [email protected].
¹⁵ Institute for Data Science and Informatics, University of Missouri - Columbia, Columbia, MO, USA. [email protected].
¹⁶ Department of Biomedical Engineering, Center for the Investigation of Membrane Excitability Disorders, Cardiac Bioelectricity and Arrhythmia Center, Washington University, St. Louis, MO, USA. [email protected].

^# Contributed equally.

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.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Calcium* / metabolism
Cell Membrane / metabolism
Large-Conductance Calcium-Activated Potassium Channels* / chemistry

Substances

Large-Conductance Calcium-Activated Potassium Channels
Calcium

Abstract

Publication types

MeSH terms

Substances

Grants and funding