A422T mutation in HERG potassium channel retained in ER is rescurable by pharmacologic or molecular chaperones

Biochemical and Biophysical Research Communications
Jia GuoZhao Zhang

Abstract

In the present study, we characterized biologic and electrophysiologic consequences of A422T mutation in HERG K(+) channel and the role of pharmacologic or molecular chaperons by employing a heterogeneous expression system in HEK 293 cells. It was found that A422T mutation led to a marked decrease in whole-cell recording currents, and that a complexly glycosylated form protein band at 155 kDa was missing by Western blotting analysis compared to wild type (WT). And the mutant protein was mainly located in the cytoplasm as illustrated in immunocytochemical assay, indicating that the mutation underwent a trafficking defect. In addition, A422T mutation exerted remarkable dominant-negative suppression on WT, resulting in the alteration in the kinetic processes. Strikingly, trafficking-deficient A422T mutation was partially rescued by incubating the cells at a lower temperature, administration of pharmacologic chaperon, E4031 or overexpression of a chaperon molecule, Hsp90, but not Hsp70. In conclusion, missense A422T mutation in HERG K(+) channel results in its trafficking defect, which is rescurable by pharmacologic or molecular chaperones.

References

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Citations

Oct 21, 2016·Journal of Arrhythmia·Jennifer L SmithBrian P Delisle
Jun 12, 2013·Journal of Cellular and Molecular Medicine·Yanhong GaoLiping Nie
May 21, 2020·Frontiers in Pharmacology·Kathryn R BrewerCharles R Sanders
Oct 20, 2019·Cardiovascular Research·Matthew D PerryJamie I Vandenberg

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