Analysis of the cyclic nucleotide binding domain of the HERG potassium channel and interactions with KCNE2

Citation
J. Cui et al., Analysis of the cyclic nucleotide binding domain of the HERG potassium channel and interactions with KCNE2, J BIOL CHEM, 276(20), 2001, pp. 17244-17251
Citations number
33
Categorie Soggetti
Biochemistry & Biophysics
Journal title
JOURNAL OF BIOLOGICAL CHEMISTRY
ISSN journal
00219258 → ACNP
Volume
276
Issue
20
Year of publication
2001
Pages
17244 - 17251
Database
ISI
SICI code
0021-9258(20010518)276:20<17244:AOTCNB>2.0.ZU;2-E
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 ki nase A. To assess the physiological significance of cAMP binding to HERG, w e introduced mutations to disrupt the cyclic nucleotide binding domain. Eig ht mutants including two naturally occurring LQT2 mutants V822M and R823W w ere constructed. Relative cAMP binding capacity was reduced or absent in CN BD mutants. Mutant homotetramers carry little or no K+ current despite norm al protein abundance and surface expression. Co-expression of mutant and wi ld-type HERG; resulted in currents with altered voltage dependence but with out 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 accessor y protein that associates with HERG, however, conferred a partially dominan t current suppression by CNBD mutants. Thus KCNE2 plays a pivotal role in d etermining the phenotypic severity of some forms of LQT2, which suggests th at the CNBD of HERG may be involved in its interaction with KCNE2.