BK channel modulation by positively charged peptides and auxiliary γ subunits mediated by the Ca2+-bowl site

被引：1

作者：

Chen, Guanxing ^{[1
]}

Li, Qin ^{[1
]}

Webb, Timothy I. ^{[3
]}

Hollywood, Mark A. ^{[3
]}

Yan, Jiusheng ^{[1
,2
]}

机构：

[1] Univ Texas MD Anderson Canc Ctr, Dept Anesthesiol & Perioperat Med, Houston, TX 77030 USA

[2] MD Anderson UT Hlth Grad Sch Biomed Sci, Neurosci & Biochem & Cell Biol Grad Programs, Houston, TX 77030 USA

[3] Dundalk Inst Technol, Smooth Muscle Res Ctr, Dundalk, Ireland

来源：

JOURNAL OF GENERAL PHYSIOLOGY | 2023年 / 155卷 / 06期

基金：

美国国家卫生研究院; 爱尔兰科学基金会;

关键词：

LARGE-CONDUCTANCE; POTASSIUM CHANNELS; K+ CHANNELS; ACTIVATION; VOLTAGE; BINDING; DOMAIN; BETA;

D O I：

10.1085/jgp.202213237

中图分类号：

Q4 [生理学];

学科分类号：

071003 ;

摘要：

The intracellular C-terminal positively charged regions of the gamma subunits play important roles in BK channel modulation. This work identifies positively charged peptides as BK channel modulators and reveals a role for the Ca2+-bowl site in BK channel modulation by positively charged peptides and the auxiliary gamma subunits. The large-conductance, Ca2+-, and voltage-activated K+ (BK) channel consists of the pore-forming alpha (BK alpha) subunit and regulatory beta and gamma subunits. The gamma 1-3 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 gamma subunits play important roles in BK channel modulation. In this study, we found that the intracellular C-terminal region of BK alpha is indispensable in BK channel modulation by the gamma 1 subunit. Notably, synthetic peptide mimics of the gamma 1-3 subunits' C-terminal positively charged regions caused 30-50 mV shifts in BK alpha 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 gamma subunits in BK channel modulation was reduced by charge neutralization of the Ca2+-bowl site. However, BK channel modulation by the gamma 1 subunit was little affected by high ionic strength and the positively charged peptide remained effective in BK channel modulation in the presence of the gamma 1 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 gamma subunits.

引用

页数：15