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The binding site for channel blockers that rescue misprocessed human long QT syndrome type 2 ether-a-gogo-related gene (HERG) mutations.
J Biol Chem. 2002 Feb 15; 277(7):4989-98.JB

Abstract

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 I(Kr) 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.

Authors+Show Affiliations

Rammelkamp Center for Education and Research, MetroHealth Campus, Case Western Reserve University, Cleveland, Ohio 44109, USA. eficker@metrohealth.orgNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

11741928

Citation

Ficker, Eckhard, et al. "The Binding Site for Channel Blockers That Rescue Misprocessed Human Long QT Syndrome Type 2 Ether-a-gogo-related Gene (HERG) Mutations." The Journal of Biological Chemistry, vol. 277, no. 7, 2002, pp. 4989-98.
Ficker E, Obejero-Paz CA, Zhao S, et al. The binding site for channel blockers that rescue misprocessed human long QT syndrome type 2 ether-a-gogo-related gene (HERG) mutations. J Biol Chem. 2002;277(7):4989-98.
Ficker, E., Obejero-Paz, C. A., Zhao, S., & Brown, A. M. (2002). The binding site for channel blockers that rescue misprocessed human long QT syndrome type 2 ether-a-gogo-related gene (HERG) mutations. The Journal of Biological Chemistry, 277(7), 4989-98.
Ficker E, et al. The Binding Site for Channel Blockers That Rescue Misprocessed Human Long QT Syndrome Type 2 Ether-a-gogo-related Gene (HERG) Mutations. J Biol Chem. 2002 Feb 15;277(7):4989-98. PubMed PMID: 11741928.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The binding site for channel blockers that rescue misprocessed human long QT syndrome type 2 ether-a-gogo-related gene (HERG) mutations. AU - Ficker,Eckhard, AU - Obejero-Paz,Carlos A, AU - Zhao,Shuxia, AU - Brown,Arthur M, Y1 - 2001/12/10/ PY - 2001/12/14/pubmed PY - 2002/3/22/medline PY - 2001/12/14/entrez SP - 4989 EP - 98 JF - The Journal of biological chemistry JO - J. Biol. Chem. VL - 277 IS - 7 N2 - 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 I(Kr) 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. SN - 0021-9258 UR - https://www.unboundmedicine.com/medline/citation/11741928/The_binding_site_for_channel_blockers_that_rescue_misprocessed_human_long_QT_syndrome_type_2_ether_a_gogo_related_gene__HERG__mutations_ L2 - http://www.jbc.org/cgi/pmidlookup?view=long&pmid=11741928 DB - PRIME DP - Unbound Medicine ER -