|
|
|
|||||||
|
|||||||||
J. Biol. Chem., Vol. 277, Issue 7, 4989-4998, February 15, 2002
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
From the Rammelkamp Center for Education and Research, MetroHealth
Campus, Case Western Reserve University, Cleveland, Ohio 44109, and the
§ Department of Physiology and Biophysics, Case Western
Reserve University, Cleveland, Ohio 44106
Mutations in the human
ether-a-gogo-related gene (HERG) K+ channel
gene cause chromosome 7-linked long QT syndrome type 2 (LQT2), which is
characterized by a prolonged QT interval in the electrocardiogram and
an increased susceptibility to life-threatening cardiac arrhythmias. LQT2 mutations produce loss-of-function phenotypes and reduce IKr currents either by the heteromeric assembly
of non- or malfunctioning channel subunits with wild type subunits at
the cell surface or by retention of misprocessed mutant HERG channels
in the endoplasmic reticulum. Misprocessed mutations often encode for
channel proteins that are functional upon incorporation into the plasma
membrane. As a result the pharmacological correction of folding defects and restoration of protein function are of considerable interest. Here
we report that the trafficking-deficient pore mutation HERG G601S was
rescued by a series of HERG channel blockers that increased cell
surface expression. Rescue by these pharmacological chaperones varied
directly with their blocking potency. We used structure-activity relationships and site-directed mutagenesis to define the binding site
of the pharmacological chaperones. We found that binding occurred in
the inner cavity and correlated with hydrophobicity and cationic
charge. Rescue was domain-restricted because the trafficking of two
misprocessed mutations in the C terminus, HERG F805C and HERG R823W,
was not restored by channel blockers. Our findings represent a first
step toward the design of pharmacological chaperones that will rescue
HERG K+ channels without block.
The Binding Site for Channel Blockers That Rescue Misprocessed
Human Long QT Syndrome Type 2 ether-a-gogo-related Gene
(HERG) Mutations*
,
*
This work was supported by National Institutes of Health
Grants HL 36930, HL 61642, and DK 54178 (to A. M. B.) and a
grant-in-aid from the American Heart Association, Northeast Ohio
Affiliate (to C. A. O.-P.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Rammelkamp Center,
MetroHealth Medical Center, 2500 MetroHealth Dr., Cleveland, OH
44109. Tel.: 216-778-8977; Fax: 216-778-8282; E-mail:
eficker@metrohealth.org.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
 |
|
  L. Wang, A. T. Dennis, P. Trieu, F. Charron, N. Ethier, T. E. Hebert, X. Wan, and E. Ficker Intracellular Potassium Stabilizes Human Ether-a-go-go-Related Gene Channels for Export from Endoplasmic Reticulum Mol. Pharmacol., April 1, 2009; 75(4): 927 - 937. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. M. Noorwez, D. A. Ostrov, J. H. McDowell, M. P. Krebs, and S. Kaushal A High-Throughput Screening Method for Small-Molecule Pharmacologic Chaperones of Misfolded Rhodopsin Invest. Ophthalmol. Vis. Sci., July 1, 2008; 49(7): 3224 - 3230. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. N. Hebert and M. Molinari In and Out of the ER: Protein Folding, Quality Control, Degradation, and Related Human Diseases Physiol Rev, October 1, 2007; 87(4): 1377 - 1408. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. E. Walker, R. Atanasiu, H. Lam, and A. Shrier Co-chaperone FKBP38 Promotes HERG Trafficking J. Biol. Chem., August 10, 2007; 282(32): 23509 - 23516. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. F. Steele, J. Eldstrom, and D. Fedida Mechanisms of cardiac potassium channel trafficking J. Physiol., July 1, 2007; 582(1): 17 - 26. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Q. Gong, M. A. Jones, and Z. Zhou Mechanisms of Pharmacological Rescue of Trafficking-defective hERG Mutant Channels in Human Long QT Syndrome J. Biol. Chem., February 17, 2006; 281(7): 4069 - 4074. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. L. Anderson, B. P. Delisle, B. D. Anson, J. A. Kilby, M. L. Will, D. J. Tester, Q. Gong, Z. Zhou, M. J. Ackerman, and C. T. January Most LQT2 Mutations Reduce Kv11.1 (hERG) Current by a Class 2 (Trafficking-Deficient) Mechanism Circulation, January 24, 2006; 113(3): 365 - 373. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Abriel and O. Staub Ubiquitylation of Ion Channels Physiology, December 1, 2005; 20(6): 398 - 407. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. J. Wilson, K. V. Quinn, F. M. Graves, M. Bitner-Glindzicz, and A. Tinker Abnormal KCNQ1 trafficking influences disease pathogenesis in hereditary long QT syndromes (LQT1) Cardiovasc Res, August 15, 2005; 67(3): 476 - 486. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. P. Delisle, J. K. Slind, J. A. Kilby, C. L. Anderson, B. D. Anson, R. C. Balijepalli, D. J. Tester, M. J. Ackerman, T. J. Kamp, and C. T. January Intragenic Suppression of Trafficking-Defective KCNH2 Channels Associated with Long QT Syndrome Mol. Pharmacol., July 1, 2005; 68(1): 233 - 240. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Akhavan, R. Atanasiu, T. Noguchi, W. Han, N. Holder, and A. Shrier Identification of the cyclic-nucleotide-binding domain as a conserved determinant of ion-channel cell-surface localization J. Cell Sci., July 1, 2005; 118(13): 2803 - 2812. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. E. Garcia-Ferreiro, D. Kerschensteiner, F. Major, F. Monje, W. Stuhmer, and L. A. Pardo Mechanism of Block of hEag1 K+ Channels by Imipramine and Astemizole J. Gen. Physiol., September 27, 2004; 124(4): 301 - 317. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Bonapace, A. Waheed, G. N. Shah, and W. S. Sly Chemical chaperones protect from effects of apoptosis-inducing mutation in carbonic anhydrase IV identified in retinitis pigmentosa 17 PNAS, August 17, 2004; 101(33): 12300 - 12305. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Q. Gong, C. L. Anderson, C. T. January, and Z. Zhou Pharmacological rescue of trafficking defective HERG channels formed by coassembly of wild-type and long QT mutant N470D subunits Am J Physiol Heart Circ Physiol, August 1, 2004; 287(2): H652 - H658. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Gouas, C. Bellocq, M. Berthet, F. Potet, S. Demolombe, A. Forhan, R. Lescasse, F. Simon, B. Balkau, I. Denjoy, et al. New KCNQ1 mutations leading to haploinsufficiency in a general population: Defective trafficking of a KvLQT1 mutant Cardiovasc Res, July 1, 2004; 63(1): 60 - 68. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. P. Delisle, B. D. Anson, S. Rajamani, and C. T. January Biology of Cardiac Arrhythmias: Ion Channel Protein Trafficking Circ. Res., June 11, 2004; 94(11): 1418 - 1428. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N.J. Winston, M.H. Johnson, J.M. McConnell, D.I. Cook, and M.L. Day Expression and Role of the Ether-a-Go-Go-Related (MERG1A) Potassium-Channel Protein During Preimplantation Mouse Development Biol Reprod, April 1, 2004; 70(4): 1070 - 1079. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Thomas, J. Kiehn, H. A Katus, and C. A Karle Defective protein trafficking in hERG-associated hereditary long QT syndrome (LQT2): molecular mechanisms and restoration of intracellular protein processing Cardiovasc Res, November 1, 2003; 60(2): 235 - 241. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. J Paavonen, H. Chapman, P. J Laitinen, H. Fodstad, K. Piippo, H. Swan, L. Toivonen, M. Viitasalo, K. Kontula, and M. Pasternack Functional characterization of the common amino acid 897 polymorphism of the cardiac potassium channel KCNH2 (HERG) Cardiovasc Res, September 1, 2003; 59(3): 603 - 611. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Ficker, A. T. Dennis, L. Wang, and A. M. Brown Role of the Cytosolic Chaperones Hsp70 and Hsp90 in Maturation of the Cardiac Potassium Channel hERG Circ. Res., June 27, 2003; 92 (12): e87 - e100. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Anantharam, A. Lewis, G. Panaghie, E. Gordon, Z. A. McCrossan, D. J. Lerner, and G. W. Abbott RNA Interference Reveals That Endogenous Xenopus MinK-related Peptides Govern Mammalian K+ Channel Function in Oocyte Expression Studies J. Biol. Chem., March 28, 2003; 278(14): 11739 - 11745. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. L Tan, C. R Bezzina, J. P.P Smits, A. O Verkerk, and A. A.M Wilde Genetic control of sodium channel function Cardiovasc Res, March 15, 2003; 57(4): 961 - 973. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Paulussen, A. Raes, G. Matthijs, D. J. Snyders, N. Cohen, and J. Aerssens A Novel Mutation (T65P) in the PAS Domain of the Human Potassium Channel HERG Results in the Long QT Syndrome by Trafficking Deficiency J. Biol. Chem., December 6, 2002; 277(50): 48610 - 48616. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. R Bezzina and H. L Tan Pharmacological rescue of mutant ion channels Cardiovasc Res, August 1, 2002; 55(2): 229 - 232. [Full Text] [PDF]
|
|
|
|
|
|
S. Rajamani, C. L. Anderson, B. D. Anson, and C. T. January Pharmacological Rescue of Human K+ Channel Long-QT2 Mutations: Human Ether-a-Go-Go-Related Gene Rescue Without Block Circulation, June 18, 2002; 105(24): 2830 - 2835. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| All ASBMB Journals | Molecular and Cellular Proteomics |
| Journal of Lipid Research | ASBMB Today |