The hERG channel is dependent upon the Hsp90α isoform for maturation and trafficking.

Molecular Pharmaceutics
Laura B PetersonBrian S J Blagg

Abstract

Heat shock protein 90 (Hsp90) has emerged as a promising therapeutic target for the treatment of cancer. Several Hsp90 inhibitors have entered clinical trials. However, some toxicological detriments have arisen, such as cardiotoxicity resulting from hERG inhibition following the administration of Hsp90 inhibitors. We sought to investigate this toxicity as hERG has been previously reported as a client protein that depends upon Hsp90 for its maturation and functional trafficking. In this study we show that hERG depends upon a single Hsp90 isoform. hERG preferentially co-immunoprecipitated with Hsp90α, and genetic knockdown of Hsp90α, but not Hsp90β, resulted in a trafficking-defective hERG channel. This study demonstrates the importance of delineating the isoform dependence of Hsp90 client proteins and provides rationale for the design of isoform-selective Hsp90 inhibitors that avoid detrimental effects.

References

Feb 2, 1999·The Journal of Physiology·K PetreccaA Shrier
May 8, 2001·Trends in Pharmacological Sciences·J I VandenbergT J Campbell
Jun 11, 2002·American Journal of Physiology. Cell Physiology·Ai-Yu GongNicholas F LaRusso
May 31, 2003·Nature Reviews. Drug Discovery·Bernard Fermini, Anthony A Fossa
Mar 15, 2005·Critical Reviews in Biochemistry and Molecular Biology·Daniel L RiggsDavid F Smith
Jun 14, 2005·Journal of Pharmacological and Toxicological Methods·Barbara A WibleArthur M Brown
Jul 30, 2005·Novartis Foundation Symposium·Arthur M Brown
Jun 16, 2007·The Journal of Biological Chemistry·Valerie E WalkerAlvin Shrier
Nov 6, 2007·Current Cancer Drug Targets·Stephanie C BishopBrian S J Blagg
Feb 21, 2008·The Journal of Biological Chemistry·Ahmed ChadliDavid O Toft
Nov 26, 2008·Progress in Biophysics and Molecular Biology·Mark J PerrinAdam P Hill
Jun 6, 2009·The Journal of Immunology : Official Journal of the American Association of Immunologists·Josetta L HoulihanJanice S Blum
Aug 6, 2009·Biochemical and Biophysical Research Communications·Jayasri NanduriNanduri R Prabhakar
Oct 29, 2009·Current Topics in Medicinal Chemistry·Y S KimJ B Trepel
Jan 9, 2010·Journal of Medicinal Chemistry·Marco A BiamonteWen-Cherng Lee
Oct 16, 2010·Cellular Microbiology·Lydia DmochewitzHolger Barth
Oct 20, 2011·Biochimica Et Biophysica Acta·Jill L Johnson

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Citations

Nov 5, 2014·Future Medicinal Chemistry·Jessica A HallBrian S J Blagg
Mar 24, 2016·Journal of Medicinal Chemistry·Vincent M CrowleyBrian S J Blagg
Apr 12, 2015·Postgraduate Medical Journal·Berengere M Dumotier
Jul 8, 2014·European Journal of Pharmacology·Hisashi Nogawa, Tomoyuki Kawai
Jan 1, 2016·The Journal of Physiology·Brian FooAlvin Shrier
Jul 29, 2016·Proceedings of the National Academy of Sciences of the United States of America·Kendrick H YimLeonard Neckers
May 27, 2015·Medicinal Research Reviews·Anuj KhandelwalBrian S J Blagg
Feb 1, 2018·Nature Communications·Anuj KhandelwalBrian S J Blagg
Dec 4, 2019·Current Cancer Drug Targets·Jackee SanchezBrian S J Blagg
Feb 16, 2020·Medicinal Research Reviews·Xingyue Ji, Zhuorong Li
Jun 12, 2013·Journal of Cellular and Molecular Medicine·Yanhong GaoLiping Nie
Oct 23, 2014·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Geoffrey I ShapiroDaruka Mahadevan
Jan 12, 2021·Journal of Medicinal Chemistry·Sanket J MishraBrian S J Blagg

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