The DOI matches its Crossref record; 53 of the 53 references it cites were found in a registry or an index.
Role of the Cytosolic Chaperones Hsp70 and Hsp90 in Maturation of the Cardiac Potassium Channel hERG
Abstract
The human ether-a-gogo –related gene (hERG) encodes the α subunit of the cardiac potassium current I Kr . Several mutations in hERG produce trafficking-deficient channels that may cause hereditary long-QT syndrome and sudden cardiac death. Although hERG currents have been studied extensively, little is known about the proteins involved in maturation and trafficking of hERG. Using immunoprecipitations, we show that the cytosolic chaperones heat shock protein (Hsp) 70 and Hsp90, but not Grp94, interact with hERG wild type (WT) during maturation. The specific Hsp90 inhibitor geldanamycin prevents maturation and increases proteasomal degradation of hERG WT, while reducing hERG currents in heterologous expression systems. In ventricular myocytes, inhibition of Hsp90 also decreases I Kr , whereas geldanamycin had no effect on I Ks or heterologously expressed Kv2.1 and Kv1.5 currents. Both Hsp90 and Hsp70 interact directly with the core-glycosylated form of hERG WT present in the endoplasmic reticulum but not the fully glycosylated, cell-surface form. For the trafficking-deficient LQT2 mutants, hERG R752W and hERG G601S, interactions with Hsp90 and Hsp70 are increased as both mutants remained tightly associated with Hsp90 and Hsp70 in the endoplasmic reticulum. Incubation at lower temperature for R752W or with the hERG blocker astemizole for G601S dissociates channel-chaperone complexes and restores trafficking. In contrast, nonfunctional but trafficking-competent hERG G628S is released from chaperone complexes during maturation comparable to WT. We conclude that Hsp90 and Hsp70 are crucial for the maturation of hERG WT as well as the retention of trafficking-deficient LQT2 mutants. The full text of this article is available online at http://www.circresaha.org.
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Cites
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Cited by
hERG K+Channels: Structure, Function, and Clinical Significance
Vandenberg, J. I., Perry, M. D., Perrin, M. J., Mann, S. A., Ke, Y., & Hill, A. P. (2012) · Physiological Reviews · doi:10.1152/physrev.00036.2011 · Cited by 696
WORKMAN, P., BURROWS, F., NECKERS, L., & ROSEN, N. (2007) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1391.012 · Cited by 521
Van Goor, F., Straley, K. S., Cao, D., González, J., Hadida, S., Hazlewood, A., Joubran, J., Knapp, T., Makings, L. R., Miller, M., et al. (2006) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00169.2005 · Cited by 512
Mechanisms of Arsenic-Induced Prolongation of Cardiac Repolarization
Ficker, E., Kuryshev, Y. A., Dennis, A. T., Obejero-Paz, C., Wang, L., Hawryluk, P., Wible, B. A., & Brown, A. M. (2004) · Molecular Pharmacology · doi:10.1124/mol.66.1.33 · Cited by 286
Self-citationRole of hsp90 and the hsp90-binding immunophilins in signalling protein movement
Pratt, W. B., Galigniana, M. D., Harrell, J. M., & DeFranco, D. B. (2004) · Cellular Signalling · doi:10.1016/j.cellsig.2004.02.004 · Cited by 285
Metadata
- Authors
- Ficker, E., Dennis, A. T., Wang, L., & Brown, A. M.
- Venue
- Circulation Research
- Published
- 2003-06-27
- Volume
- 92
- Issue
- 12
- Pages
- e87-100
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- OpenAlex
- W2134867760
- Cited by
- 323
- References
- 53
- FWCI
- 3.75
- Type
- journal article
- Language
- en
- Open access
- closed
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