Scorpion Toxin BeKm-1 Prevents Low K+ Induced Internalization of Cell-Surface hERG Channels

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Date
2015-08-07
Authors
Han, Xi
Keyword
hERG K+ channel , LQTS , Hypokalemia
Abstract
The human ether-à-go-go related gene (hERG) encoded the pore forming subunit of a K+ channel that conducts an important current for the repolarization of the cardiac action potential. Dysfunction of the hERG channel leads to abnormal cardiac activities characterized by prolongation of the QT interval, clinically known as long QT syndrome (LQTS), which can cause lethal tachyarrhythmias and sudden death. We have previously shown that hypokalemia induces a conformational change that leads to degradation of hERG channels from the plasma membrane (Guo et al., 2009). However, the molecular mechanisms for low K+ effect on hERG channels are not known and it is also unknown whether low K+-induced internalization of hERG channels can be prevented. Using various compounds that interact with hERG channels by binding to different regions of channels has been a field of interest to investigate the channel structure-function relationships. Moreover, certain high affinity hERG channel blockers such as E-4031 can rescue trafficking-detective hERG mutants (Gong et al., 2006). The hERG channel has an unusually long extracellular S5-pore linker to which the scorpion toxin BeKm-1 selectively binds. I hypothesized that the S5-pore linker contributes to the unique sensitivity of hERG channels to extracellular K+, and that BeKm-1 prevents the internalization of hERG channels induced by 0 mM [K+]o through binding to S5-pore linker. In the present study, I investigated the protective effects of the scorpion toxin, BeKm-1, on low K+-induced hERG internalization using whole-cell patch-clamp, and Western blot analysis. Our data demonstrate that BeKm-1 effectively prevents low K+-induced hERG current loss and protein degradation. Since BeKm-1 blocks hERG channels, its protective effect on low K+-induced hERG internalization has limited clinical potential. Thus, we designed ten BeKm-1 mutants to screen for peptides that can prevent hERG from low K+-induced internalization without blocking hERG conductance. Our data show that two mutants were able to rescue hERG channels in 0 mM [K+]o but do not block hERG conductance. This study extends our understanding of the structure-function relationship of hERG channels and revealed a potential novel way to protect hERG channels from low K+-induced internalization.
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