Characterization of S818L mutation in HERG C-terminus in LQT2. Modification of activation-deactivation gating properties.
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.
Nakajima
T
T
Second Department of Internal Medicine, Gunma University School of Medicine, Showa-Machi, Maebashi, Gunma 371-8511, Japan.
Kurabayashi
M
M
Ohyama
Y
Y
Kaneko
Y
Y
Furukawa
T
T
Itoh
T
T
Taniguchi
Y
Y
Tanaka
T
T
Nakamura
Y
Y
Hiraoka
M
M
Nagai
R
R
D019943:Amino Acid Substitution / Q000235:genetics*; D000818:Animals; D027682:Cation Transport Proteins; D004268:DNA-Binding Proteins; D000072237:ERG1 Potassium Channel; D004553:Electric Conductivity; D051638:Ether-A-Go-Go Potassium Channels; D005799:Genes, Dominant / Q000235:genetics; D016153:Genes, Suppressor / Q000235:genetics; D006801:Humans; D015640:Ion Channel Gating; D008133:Long QT Syndrome / Q000235:genetics*; D008564:Membrane Potentials; D008845:Microinjections; D009154:Mutation / Q000235:genetics*; D009865:Oocytes; D010641:Phenotype; D011188:Potassium / Q000378:metabolism; D015221:Potassium Channels / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D024642:Potassium Channels, Voltage-Gated; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D018075:RNA, Complementary / Q000008:administration & dosage / Q000235:genetics; D013329:Structure-Activity Relationship; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D014982:Xenopus laevis
D027682:Cation Transport Proteins; D004268:DNA-Binding Proteins; C072312:ERG protein, human; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; C092509:KCNH6 protein, human; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D018075:RNA, Complementary; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D011188:Potassium