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• W1976253229 endingPage "C85" @default.
• W1976253229 startingPage "C75" @default.
• W1976253229 abstract "The human ether-a-go-go related gene ( hERG) encodes the voltage-gated K + channel that underlies the rapidly activating delayed-rectifier current in cardiac myocytes. hERG is synthesized in the endoplasmic reticulum (ER) as an “immature” N-linked glycoprotein and is terminally glycosylated in the Golgi apparatus. Most hERG missense mutations linked to long QT syndrome type 2 (LQT2) reduce the terminal glycosylation and functional expression. We tested the hypothesis that a distinct pre-Golgi compartment negatively regulates the trafficking of some LQT2 mutations to the Golgi apparatus. We found that treating cells in nocodazole, a microtubule depolymerizing agent, altered the subcellular localization, functional expression, and glycosylation of the LQT2 mutation G601S-hERG differently from wild-type hERG (WT-hERG). G601S-hERG quickly redistributed to peripheral compartments that partially colocalized with KDEL (Lys-Asp-Glu-Leu) chaperones but not calnexin, Sec31, or the ER golgi intermediate compartment (ERGIC). Treating cells in E-4031, a drug that increases the functional expression of G601S-hERG, prevented the accumulation of G601S-hERG to the peripheral compartments and increased G601S-hERG colocalization with the ERGIC. Coexpressing the temperature-sensitive mutant G protein from vesicular stomatitis virus, a mutant N-linked glycoprotein that is retained in the ER, showed it was not restricted to the same peripheral compartments as G601S-hERG at nonpermissive temperatures. We conclude that the trafficking of G601S-hERG is negatively regulated by a microtubule-dependent compartment within the ER. Identifying mechanisms that prevent the sorting or promote the release of LQT2 channels from this compartment may represent a novel therapeutic strategy for LQT2." @default.
• W1976253229 created "2016-06-24" @default.
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• W1976253229 date "2011-07-01" @default.
• W1976253229 modified "2023-10-18" @default.
• W1976253229 title "Trafficking-deficient hERG K⁺channels linked to long QT syndrome are regulated by a microtubule-dependent quality control compartment in the ER" @default.
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• W1976253229 doi "https://doi.org/10.1152/ajpcell.00494.2010" @default.
• W1976253229 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/3129823" @default.
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