Premium
Impaired trafficking and maturation of hERG K+ channel protein by Hypoxia. Role of Hsp90 and Hsp70 chaperones
Author(s) -
Nanduri Jayasri,
Yuan Guoxiang,
Ficker Eckhard,
Prabhakar Nanduri R
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a790-c
Subject(s) - herg , hsp90 , hsp70 , heat shock protein , microbiology and biotechnology , co chaperone , hypoxia (environmental) , chemistry , biology , medicine , biochemistry , potassium channel , gene , oxygen , organic chemistry
Human ether‐a‐go‐go (hERG) K+ channels regulate resting membrane potential in a variety of cells. We have reported that hypoxia decreases hERG protein expression and attenuates hERG current densities. The effects of hypoxia were reversed by ROS scavengers. In the present study we examined whether the effects of hypoxia on hERG protein are due to defective maturation and/or trafficking of the protein. To test this possibility, we studied the impact of hypoxia on hERG processing in HEK 293 cells stably expressing hERG protein. Pulse chase studies showed that hypoxia blocks maturation of the core glycosylated form in the endoplasmic reticulum (ER) to the fully glycosylated form on the cell surface. Hypoxia also inhibited hERG protein synthesis by 50%. However, the turnover rate of the ER form was not affected by hypoxia. To test if the effects of hypoxia on maturation are due to chaperone‐hERG interactions, we determined the association of Hsp90/Hsp70 with hERG protein under hypoxia. Coimmunoprecipitation and radio labelling experiments revealed that under normoxic conditions both Hsp90 and Hsp70 interacted exclusively with newly synthesized core‐glycosylated hERG protein but not with fully glycosylated mature cell surface protein. The chaperone interactions were completely inhibited under hypoxia. These results demonstrate that hypoxia prevents maturation of the hERG protein by inhibiting chaperone interactions. Supported by NIH‐HLBI‐25830