The large-conductance, Ca2+-, and voltage-activated K+ (BK) channel consists of the pore-forming α (BKα) subunit and regulatory β and γ subunits. The γ1–3 subunits facilitate BK channel activation by shifting the voltage-dependence of channel activation toward the hyperpolarization direction by about 50–150 mV in the absence of Ca2+. We previously found that the intracellular C-terminal positively charged regions of the γ subunits play important roles in BK channel modulation. In this study, we found that the intracellular C-terminal region of BKα is indispensable in BK channel modulation by the γ1 subunit. Notably, synthetic peptide mimics of the γ1–3 subunits’ C-terminal positively charged regions caused 30–50 mV shifts in BKα channel voltage-gating toward the hyperpolarization direction. The cationic cell–penetrating HIV-1 Tat peptide exerted a similar BK channel–activating effect. The BK channel–activating effects of the synthetic peptides were reduced in the presence of Ca2+ and markedly ablated by both charge neutralization of the Ca2+-bowl site and high ionic strength, suggesting the involvement of electrostatic interactions. The efficacy of the γ subunits in BK channel modulation was reduced by charge neutralization of the Ca2+-bowl site. However, BK channel modulation by the γ1 subunit was little affected by high ionic strength and the positively charged peptide remained effective in BK channel modulation in the presence of the γ1 subunit. These findings identify positively charged peptides as BK channel modulators and reveal a role for the Ca2+-bowl site in BK channel modulation by positively charged peptides and the C-terminal positively charged regions of auxiliary γ subunits.
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5 June 2023
Article|
May 02 2023
BK channel modulation by positively charged peptides and auxiliary γ subunits mediated by the Ca2+-bowl site
Guanxing Chen
,
Guanxing Chen
(Conceptualization, Formal analysis, Investigation, Methodology, Validation, Visualization, Writing - original draft, Writing - review & editing)
1Department of Anesthesiology and Perioperative Medicine,
The University of Texas MD Anderson Cancer Center
, Houston, TX, USA
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Qin Li
,
Qin Li
(Formal analysis, Investigation, Methodology)
1Department of Anesthesiology and Perioperative Medicine,
The University of Texas MD Anderson Cancer Center
, Houston, TX, USA
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Timothy I. Webb
,
Timothy I. Webb
(Resources, Writing - review & editing)
3
The Smooth Muscle Research Centre, Dundalk Institute of Technology
, Dundalk, Ireland
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Mark A. Hollywood
,
Mark A. Hollywood
(Funding acquisition, Resources, Writing - original draft, Writing - review & editing)
3
The Smooth Muscle Research Centre, Dundalk Institute of Technology
, Dundalk, Ireland
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Jiusheng Yan
(Conceptualization, Data curation, Funding acquisition, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing - review & editing)
1Department of Anesthesiology and Perioperative Medicine,
The University of Texas MD Anderson Cancer Center
, Houston, TX, USA
2
Neuroscience and Biochemistry and Cell Biology Graduate Programs, MD Anderson UT Health Graduate School of Biomedical Sciences
, Houston, TX, USA
Correspondence to Jiusheng Yan: jyan1@mdanderson.org
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Guanxing Chen
Conceptualization, Formal analysis, Investigation, Methodology, Validation, Visualization, Writing - original draft, Writing - review & editing
1Department of Anesthesiology and Perioperative Medicine,
The University of Texas MD Anderson Cancer Center
, Houston, TX, USA
Qin Li
Formal analysis, Investigation, Methodology
1Department of Anesthesiology and Perioperative Medicine,
The University of Texas MD Anderson Cancer Center
, Houston, TX, USA
Timothy I. Webb
Resources, Writing - review & editing
3
The Smooth Muscle Research Centre, Dundalk Institute of Technology
, Dundalk, Ireland
Mark A. Hollywood
Funding acquisition, Resources, Writing - original draft, Writing - review & editing
3
The Smooth Muscle Research Centre, Dundalk Institute of Technology
, Dundalk, Ireland
Jiusheng Yan
Conceptualization, Data curation, Funding acquisition, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing - review & editing
1Department of Anesthesiology and Perioperative Medicine,
The University of Texas MD Anderson Cancer Center
, Houston, TX, USA
2
Neuroscience and Biochemistry and Cell Biology Graduate Programs, MD Anderson UT Health Graduate School of Biomedical Sciences
, Houston, TX, USA
Correspondence to Jiusheng Yan: jyan1@mdanderson.org
Disclosures: The authors declare no competing interests exist.
Received:
July 30 2022
Revision Received:
January 12 2023
Revision Received:
April 04 2023
Revision Received:
April 06 2023
Accepted:
April 13 2023
Online ISSN: 1540-7748
Print ISSN: 0022-1295
Funding
Funder(s):
National Institutes of Health
- Award Id(s): NS078152,GM127332
Funder(s):
Science Foundation Ireland
- Award Id(s): 21/FFP-A/9209
© 2023 Chen et al.
2023
Chen et al.
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
J Gen Physiol (2023) 155 (6): e202213237.
Article history
Received:
July 30 2022
Revision Received:
January 12 2023
Revision Received:
April 04 2023
Revision Received:
April 06 2023
Accepted:
April 13 2023
Citation
Guanxing Chen, Qin Li, Timothy I. Webb, Mark A. Hollywood, Jiusheng Yan; BK channel modulation by positively charged peptides and auxiliary γ subunits mediated by the Ca2+-bowl site. J Gen Physiol 5 June 2023; 155 (6): e202213237. doi: https://doi.org/10.1085/jgp.202213237
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