The importance of the rapid component of the delayed-rectifier potassium current (IKr) in maintaining normal cardiac rhythm is now well established. However, before the description of IKr in 1990, the identity of the individual ionic currents involved in cardiac repolarization remained elusive. Early fundamental electrophysiology theorized that the opening of voltage-gated potassium channels towards the end of the cardiac action potential was likely to underlie the repolarization, as occurs in neurons. In 1969, Noble and Tsien postulated that, given that the activation time-course of the cardiac delayed-rectifier potassium current (IK) could be fit with a biexponential function representing two distinct time-dependent activating components, at least two different currents must be responsible for cardiac repolarization. Through the pharmacological isolation of IKr in guinea pig cardiomyocytes, Sanguinetti and Jurkiewicz were able to confirm this hypothesis, and named the two currents as the rapid (IKr) and slow (IKs) components of IK. Remarkably, the kinetics of IKr measured by Sanguinetti and Jurkiewicz seemed to be almost identical to recordings made by Shibasaki in rabbit sinoatrial node cells a few years earlier, raising the possibility that IKr was involved in both normal repolarization and intrinsic pacemaker activity in the heart.

Following this discovery by Sanguinetti and Jurkiewicz, the KCNH2 gene that encodes the major potassium channel protein responsible for IKr, known as hERG (or Kv11.1), was successfully cloned from a human hippocampal cDNA library. Using heterologous overexpression and patch clamp electrophysiology experiments, parallel studies by the Robertson and Sanguinetti groups showed that the recombinant hERG currents closely resembled the IKr observed in guinea pig cardiomyocytes. Both exhibited slow activation and deactivation kinetics, with unusually fast inactivation and characteristic resurgent tail currents, a result of rapid recovery from the inactivated state. Many publications ensued, establishing a model for hERG gating, revealing how IKr efficiently repolarizes the myocardium and protects against pro-arrhythmic afterdepolarizations.