Key result
Deletion of the HERG C-terminal 147 amino acids exposes an RGR endoplasmic reticulum retention signal that abolishes I_Kr current by preventing protein trafficking to the cell surface.
Why the study?
Does deletion or mutation of the C-terminal amino acids of HERG affect I_Kr current and protein trafficking?
Population
In vitro cell models expressing wild-type and mutant HERG channels (HERG_Δ147, HERG_Δ159, HERG_Δ147-LGL)
Comparison
Deletion or mutation of the C-terminal amino… vs Wild-type HERG
Design
Preclinical
Authors
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Supports mechanistic basis for LQT2 trafficking defects; leaves open therapeutic targeting of ER signals pending clinical validation.
Does deletion or mutation of the C-terminal amino acids of HERG affect I_Kr current and protein trafficking?
The study identifies that a key function of the HERG C-terminal 104 amino acids is to mask an ER retention signal, explaining the molecular mechanism of defective trafficking in LQT2.
Kupershmidt et al. (2002) studied Long QT syndrome (LQT2). HERG C-terminal deletions and mutations vs. Wild-type HERG was evaluated on I_Kr current amplitude and surface protein expression. Deletion of the HERG C-terminal 147 amino acids exposes an RGR endoplasmic reticulum retention signal that abolishes I_Kr current by preventing protein trafficking to the cell surface.
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