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J. Biol. Chem., Vol. 276, Issue 20, 17244-17251, May 18, 2001
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From the Section of Molecular Cardiology, Departments of Medicine
and Molecular Pharmacology, Albert Einstein College of Medicine,
Bronx, New York 10461
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.
Analysis of the Cyclic Nucleotide Binding Domain of the HERG
Potassium Channel and Interactions with KCNE2*
*
This work was supported by National Institutes of Health
Grant NHLBI R01 HL 57388 (to T. V. M).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. Tel.: 718-430-3370;
Fax: 718-430-8989; E-mail: mcdonald@aecom.yu.edu.
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