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 I-Kr, with the consequence that mutations in HERG prolong the QT interval by reducing I-Kr. The elementary properties of HERG are unknown, and as a test of the hypothesis that HERG produces I-Kr, we compared their elementary properties. Methods and Results We injected HERC 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 Ins 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 I-Kr is similar, consistent with HERG being an important component of I-Kr. The pharmacology is also similar: dofetilide appears to primarily block activated channels and has a much lower affinity for closed and inactivated channels.