Characterization of S818L mutation in HERG C-terminus in LQT2. Modification of activation-deactivation gating properties

T Nakajima; M Kurabayashi; Y Ohyama; Y Kaneko; T Furukawa; T Itoh; Y Taniguchi; T Tanaka; Y Nakamura; M Hiraoka; R Nagai

doi:10.1016/s0014-5793(00)01988-8

Characterization of S818L mutation in HERG C-terminus in LQT2. Modification of activation-deactivation gating properties

FEBS Lett. 2000 Sep 15;481(2):197-203. doi: 10.1016/s0014-5793(00)01988-8.

Authors

T Nakajima¹, M Kurabayashi, Y Ohyama, Y Kaneko, T Furukawa, T Itoh, Y Taniguchi, T Tanaka, Y Nakamura, M Hiraoka, R Nagai

Affiliation

¹ Second Department of Internal Medicine, Gunma University School of Medicine, Showa-Machi, Maebashi, Gunma 371-8511, Japan.

PMID: 10996323
DOI: 10.1016/s0014-5793(00)01988-8

Abstract

We examined the mechanism(s) for HERG channel dysfunction in an S818L mutation in the HERG C-terminus using the heterologous expression system in Xenopus oocytes. Injection of S818L cRNA alone did not produce expressed currents. Coinjection of an equal amount of S818L cRNA with wild-type (WT) cRNA into oocytes did not exhibit apparent dominant-negative suppression. However, coinjection of excess amounts of S818L cRNAs with WT cRNA into oocytes decreased HERG current amplitudes and shifted the voltage dependence of activation to negative potentials, accelerated its activation and deactivation. The data suggest that S818L alone cannot form functional channels, whereas S818L subunits can, at least in part, coassemble with WT subunits to form heterotetrameric functional channels, and imply that the HERG C-terminus may contain a domain involving the activation-deactivation process of the channel. These findings may provide new insights into the structure-function relationships of the HERG C-terminus.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Substitution / genetics*
Animals
Cation Transport Proteins*
DNA-Binding Proteins*
ERG1 Potassium Channel
Electric Conductivity
Ether-A-Go-Go Potassium Channels
Genes, Dominant / genetics
Genes, Suppressor / genetics
Humans
Ion Channel Gating*
Long QT Syndrome / genetics*
Membrane Potentials
Microinjections
Mutation / genetics*
Oocytes
Phenotype
Potassium / metabolism
Potassium Channels / chemistry
Potassium Channels / genetics*
Potassium Channels / metabolism*
Potassium Channels, Voltage-Gated*
Protein Binding
Protein Structure, Quaternary
RNA, Complementary / administration & dosage
RNA, Complementary / genetics
Structure-Activity Relationship
Trans-Activators*
Transcriptional Regulator ERG
Xenopus laevis

Substances

Cation Transport Proteins
DNA-Binding Proteins
ERG protein, human
ERG1 Potassium Channel
Ether-A-Go-Go Potassium Channels
KCNH2 protein, human
KCNH6 protein, human
Potassium Channels
Potassium Channels, Voltage-Gated
RNA, Complementary
Trans-Activators
Transcriptional Regulator ERG
Potassium