[K(+)](o)-dependent change in conformation of the HERG1 long QT mutation N629D channel results in partial reversal of the in vitro disease phenotype.
OBJECTIVE
We hypothesized that exposure of N629D/wildtype channels to transient increases in [K(+)](o) could alter the conformation of the outer vestibule and thus reverse the disease phenotype. N629D is a recently described mutation of the HERG1 gene that causes familial long QT syndrome. This mutation alters the pore signature sequence resulting in loss of K(+) selectivity. Previous studies have reported that enforced occupancy of [K(+)](o) at sites near the selectivity filter alters the conformation/folding of the outer vestibule of the Kv2.1 channel.


METHODS
Since the long QT syndrome is manifest in individuals who are heterozygous for this HERG trait, we co-expressed N629D and the wildtype at equimolar concentrations.


RESULTS
Co-expression of N629D/wildtype in Xenopus oocytes and mammalian cells resulted in a channel with a positive shift in reversal potential and a loss in the outward tail current, relative to the wildtype. Exposure of the N629D/wildtype to transient increases in [K(+)](o) from 5 to 40 mM/l changed the tail current from inward to outward during repolarization and restored the reversal potential to values similar to the wildtype. These findings in Xenopus oocytes were also seen when N620D/wildtype channels were expressed in mammalian cells. These [K(+)](o)-dependent changes persisted for hours after the [K(+)](o) was returned to 2.5 mM. This potential therapeutic effect began with increases in [K(+)](o) from 2.5 to 5 mM.


CONCLUSIONS
This study reports a novel therapeutic strategy and mechanism to partially restore physiologic function in this HERG LQTS mutation.
Teng
Guo Qi
GQ
Department of Medicine, University of Calgary, Alberta, Canada.
Lees-Miller
James P
JP
Duan
Yanjun
Y
Li
Bao-Tsen
BT
Li
Pin
P
Duff
Henry J
HJ
D000818:Animals; D027682:Cation Transport Proteins; D004594:Electrophysiology; D051638:Ether-A-Go-Go Potassium Channels; D005260:Female; D008133:Long QT Syndrome / Q000235:genetics* / Q000503:physiopathology; D009154:Mutation; D009865:Oocytes / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010641:Phenotype; D011188:Potassium / Q000494:pharmacology / Q000502:physiology*; D015221:Potassium Channels / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D024642:Potassium Channels, Voltage-Gated; D014981:Xenopus
D027682:Cation Transport Proteins; D051638:Ether-A-Go-Go Potassium Channels; C092509:KCNH6 protein, human; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D011188:Potassium