Analysis of the Cyclic Nucleotide Binding Domain of the HERG Potassium Channel and Interactions with KCNE2

Jie Cui, Anna Kagan, Danmei Qin, Jehu Mathew, Yonathan F. Melman, Thomas V. McDonald

Research output: Contribution to journalArticle

79 Citations (Scopus)

Abstract

Mutations in the cyclic nucleotide binding domain (CNBD) of the human ether-a-go-go-related gene (HERG) K+ channel are associated with LQT2, a form of hereditary Long QT syndrome (LQTS). Elevation of cAMP can modulate HERG K+ channels both by direct binding and indirect regulation through protein kinase A. To assess the physiological significance of cAMP binding to HERG, we introduced mutations to disrupt the cyclic nucleotide binding domain. Eight mutants including two naturally occurring LQT2 mutants V822M and R823W were constructed. Relative cAMP binding capacity was reduced or absent in CNBD mutants. Mutant homotetramers carry little or no K+ current despite normal protein abundance and surface expression. Co-expression of mutant and wild-type HERG resulted in currents with altered voltage dependence but without dominant current suppression. The data from co-expression of V822M and wild-type HERG best fit a model where one normal subunit within a tetramer allows nearly normal current expression. The presence of KCNE2, an accessory protein that associates with HERG, however, conferred a partially dominant current suppression by CNBD mutants. Thus KCNE2 plays a pivotal role in determining the phenotypic severity of some forms of LQT2, which suggests that the CNBD of HERG may be involved in its interaction with KCNE2.

Original languageEnglish (US)
Pages (from-to)17244-17251
Number of pages8
JournalJournal of Biological Chemistry
Volume276
Issue number20
DOIs
StatePublished - May 18 2001
Externally publishedYes

Fingerprint

Cyclic Nucleotides
Potassium Channels
Ether
Genes
Long QT Syndrome
Mutation
Accessories
Cyclic AMP-Dependent Protein Kinases
Membrane Proteins
Proteins
Electric potential

ASJC Scopus subject areas

  • Biochemistry

Cite this

Analysis of the Cyclic Nucleotide Binding Domain of the HERG Potassium Channel and Interactions with KCNE2. / Cui, Jie; Kagan, Anna; Qin, Danmei; Mathew, Jehu; Melman, Yonathan F.; McDonald, Thomas V.

In: Journal of Biological Chemistry, Vol. 276, No. 20, 18.05.2001, p. 17244-17251.

Research output: Contribution to journalArticle

Cui, Jie ; Kagan, Anna ; Qin, Danmei ; Mathew, Jehu ; Melman, Yonathan F. ; McDonald, Thomas V. / Analysis of the Cyclic Nucleotide Binding Domain of the HERG Potassium Channel and Interactions with KCNE2. In: Journal of Biological Chemistry. 2001 ; Vol. 276, No. 20. pp. 17244-17251.
@article{029e93d01fa043f7ba6739fbaf79a427,
title = "Analysis of the Cyclic Nucleotide Binding Domain of the HERG Potassium Channel and Interactions with KCNE2",
abstract = "Mutations in the cyclic nucleotide binding domain (CNBD) of the human ether-a-go-go-related gene (HERG) K+ channel are associated with LQT2, a form of hereditary Long QT syndrome (LQTS). Elevation of cAMP can modulate HERG K+ channels both by direct binding and indirect regulation through protein kinase A. To assess the physiological significance of cAMP binding to HERG, we introduced mutations to disrupt the cyclic nucleotide binding domain. Eight mutants including two naturally occurring LQT2 mutants V822M and R823W were constructed. Relative cAMP binding capacity was reduced or absent in CNBD mutants. Mutant homotetramers carry little or no K+ current despite normal protein abundance and surface expression. Co-expression of mutant and wild-type HERG resulted in currents with altered voltage dependence but without dominant current suppression. The data from co-expression of V822M and wild-type HERG best fit a model where one normal subunit within a tetramer allows nearly normal current expression. The presence of KCNE2, an accessory protein that associates with HERG, however, conferred a partially dominant current suppression by CNBD mutants. Thus KCNE2 plays a pivotal role in determining the phenotypic severity of some forms of LQT2, which suggests that the CNBD of HERG may be involved in its interaction with KCNE2.",
author = "Jie Cui and Anna Kagan and Danmei Qin and Jehu Mathew and Melman, {Yonathan F.} and McDonald, {Thomas V.}",
year = "2001",
month = "5",
day = "18",
doi = "10.1074/jbc.M010904200",
language = "English (US)",
volume = "276",
pages = "17244--17251",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "20",

}

TY - JOUR

T1 - Analysis of the Cyclic Nucleotide Binding Domain of the HERG Potassium Channel and Interactions with KCNE2

AU - Cui, Jie

AU - Kagan, Anna

AU - Qin, Danmei

AU - Mathew, Jehu

AU - Melman, Yonathan F.

AU - McDonald, Thomas V.

PY - 2001/5/18

Y1 - 2001/5/18

N2 - Mutations in the cyclic nucleotide binding domain (CNBD) of the human ether-a-go-go-related gene (HERG) K+ channel are associated with LQT2, a form of hereditary Long QT syndrome (LQTS). Elevation of cAMP can modulate HERG K+ channels both by direct binding and indirect regulation through protein kinase A. To assess the physiological significance of cAMP binding to HERG, we introduced mutations to disrupt the cyclic nucleotide binding domain. Eight mutants including two naturally occurring LQT2 mutants V822M and R823W were constructed. Relative cAMP binding capacity was reduced or absent in CNBD mutants. Mutant homotetramers carry little or no K+ current despite normal protein abundance and surface expression. Co-expression of mutant and wild-type HERG resulted in currents with altered voltage dependence but without dominant current suppression. The data from co-expression of V822M and wild-type HERG best fit a model where one normal subunit within a tetramer allows nearly normal current expression. The presence of KCNE2, an accessory protein that associates with HERG, however, conferred a partially dominant current suppression by CNBD mutants. Thus KCNE2 plays a pivotal role in determining the phenotypic severity of some forms of LQT2, which suggests that the CNBD of HERG may be involved in its interaction with KCNE2.

AB - Mutations in the cyclic nucleotide binding domain (CNBD) of the human ether-a-go-go-related gene (HERG) K+ channel are associated with LQT2, a form of hereditary Long QT syndrome (LQTS). Elevation of cAMP can modulate HERG K+ channels both by direct binding and indirect regulation through protein kinase A. To assess the physiological significance of cAMP binding to HERG, we introduced mutations to disrupt the cyclic nucleotide binding domain. Eight mutants including two naturally occurring LQT2 mutants V822M and R823W were constructed. Relative cAMP binding capacity was reduced or absent in CNBD mutants. Mutant homotetramers carry little or no K+ current despite normal protein abundance and surface expression. Co-expression of mutant and wild-type HERG resulted in currents with altered voltage dependence but without dominant current suppression. The data from co-expression of V822M and wild-type HERG best fit a model where one normal subunit within a tetramer allows nearly normal current expression. The presence of KCNE2, an accessory protein that associates with HERG, however, conferred a partially dominant current suppression by CNBD mutants. Thus KCNE2 plays a pivotal role in determining the phenotypic severity of some forms of LQT2, which suggests that the CNBD of HERG may be involved in its interaction with KCNE2.

UR - http://www.scopus.com/inward/record.url?scp=0035907235&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0035907235&partnerID=8YFLogxK

U2 - 10.1074/jbc.M010904200

DO - 10.1074/jbc.M010904200

M3 - Article

C2 - 11278781

AN - SCOPUS:0035907235

VL - 276

SP - 17244

EP - 17251

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 20

ER -