Molecular physiology and pharmacology of HERG. Single-channel currents and block by dofetilide.
BACKGROUND
The human ether-a-go-go-related gene (HERG) is one locus for the hereditary long-QT syndrome. A hypothesis is that HERG produces the repolarizing cardiac potassium current IKr with the consequence that mutations in HERG prolong the QT interval by reducing IKr. The elementary properties of HERG are unknown, and as a test of the hypothesis that HERG produces IKr, we compared their elementary properties.


RESULTS
We injected HERG cRNA into Xenopus oocytes and measured currents from single channels or current variance from the noise produced by ensembles of channels recorded from macro patches. Single-channel conductance was dependent on the extracellular potassium concentration ([K]o). At physiological [K]o, it was 2 picosiemens (pS), and at 100 mmol/L [K]o, it was 10 pS. Openings occurred in bursts with a mean duration of 26 ms at -100 mV. Mean open time was 3.2 ms and closed times were 1.0 and 26 ms. In excised macro patches, HERG currents were blocked by the class III antiarrhythmic drug dofetilide, with an IC50 of 35 nmol/L. Dofetilide block was slow and greatly attenuated at positive potentials at which HERG rectifies.


CONCLUSIONS
The microscopic physiology of HERG and IKr is similar, consistent with HERG being an important component of IKr. The pharmacology is also similar; dofetilide appears to primarily block activated channels and has a much lower affinity for closed and inactivated channels.
Kiehn
J
J
Rammelkamp Center for Research, Case Western Reserve University, Cleveland, Ohio 44109-1998, USA.
Lacerda
A E
AE
Wible
B
B
Brown
A M
AM
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D016477:Artifacts; D027682:Cation Transport Proteins; D004268:DNA-Binding Proteins; D000072237:ERG1 Potassium Channel; D004553:Electric Conductivity; D004594:Electrophysiology; D051638:Ether-A-Go-Go Potassium Channels; D005260:Female; D006801:Humans; D007473:Ion Channels / Q000037:antagonists & inhibitors* / Q000502:physiology*; D008967:Molecular Biology / Q000379:methods; D009865:Oocytes; D010627:Phenethylamines / Q000494:pharmacology*; D011188:Potassium / Q000502:physiology; D015221:Potassium Channels / Q000235:genetics*; D024642:Potassium Channels, Voltage-Gated; D013449:Sulfonamides / Q000494:pharmacology*; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D014981:Xenopus
D000889:Anti-Arrhythmia Agents; D027682:Cation Transport Proteins; D004268:DNA-Binding Proteins; C072312:ERG protein, human; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D007473:Ion Channels; C000606913:KCNH2 protein, human; C092509:KCNH6 protein, human; D010627:Phenethylamines; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D013449:Sulfonamides; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; C063533:dofetilide; D011188:Potassium