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BK channel modulation by positively charged peptides and auxiliary γ subunits mediated by the Ca(2+)-bowl site

The large-conductance, Ca(2+)-, 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...

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Autores principales: Chen, Guanxing, Li, Qin, Webb, Timothy I., Hollywood, Mark A., Yan, Jiusheng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Rockefeller University Press 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10163825/
https://www.ncbi.nlm.nih.gov/pubmed/37130264
http://dx.doi.org/10.1085/jgp.202213237
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author Chen, Guanxing
Li, Qin
Webb, Timothy I.
Hollywood, Mark A.
Yan, Jiusheng
author_facet Chen, Guanxing
Li, Qin
Webb, Timothy I.
Hollywood, Mark A.
Yan, Jiusheng
author_sort Chen, Guanxing
collection PubMed
description The large-conductance, Ca(2+)-, 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 Ca(2+). 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 Ca(2+) and markedly ablated by both charge neutralization of the Ca(2+)-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 Ca(2+)-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 Ca(2+)-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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spelling pubmed-101638252023-11-02 BK channel modulation by positively charged peptides and auxiliary γ subunits mediated by the Ca(2+)-bowl site Chen, Guanxing Li, Qin Webb, Timothy I. Hollywood, Mark A. Yan, Jiusheng J Gen Physiol Article The large-conductance, Ca(2+)-, 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 Ca(2+). 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 Ca(2+) and markedly ablated by both charge neutralization of the Ca(2+)-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 Ca(2+)-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 Ca(2+)-bowl site in BK channel modulation by positively charged peptides and the C-terminal positively charged regions of auxiliary γ subunits. Rockefeller University Press 2023-05-02 /pmc/articles/PMC10163825/ /pubmed/37130264 http://dx.doi.org/10.1085/jgp.202213237 Text en © 2023 Chen et al. https://creativecommons.org/licenses/by-nc-sa/4.0/http://www.rupress.org/terms/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/).
spellingShingle Article
Chen, Guanxing
Li, Qin
Webb, Timothy I.
Hollywood, Mark A.
Yan, Jiusheng
BK channel modulation by positively charged peptides and auxiliary γ subunits mediated by the Ca(2+)-bowl site
title BK channel modulation by positively charged peptides and auxiliary γ subunits mediated by the Ca(2+)-bowl site
title_full BK channel modulation by positively charged peptides and auxiliary γ subunits mediated by the Ca(2+)-bowl site
title_fullStr BK channel modulation by positively charged peptides and auxiliary γ subunits mediated by the Ca(2+)-bowl site
title_full_unstemmed BK channel modulation by positively charged peptides and auxiliary γ subunits mediated by the Ca(2+)-bowl site
title_short BK channel modulation by positively charged peptides and auxiliary γ subunits mediated by the Ca(2+)-bowl site
title_sort bk channel modulation by positively charged peptides and auxiliary γ subunits mediated by the ca(2+)-bowl site
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10163825/
https://www.ncbi.nlm.nih.gov/pubmed/37130264
http://dx.doi.org/10.1085/jgp.202213237
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