Mutant hERG channel traffic jam. Focus on “Pharmacological correction of long QT-linked mutations in KCNH2 (hERG) increases the trafficking of Kv11.1 channels stored in the transitional endoplasmic reticulum”

Abstract

ION CHANNELS ARE MACROMOLECULAR pore-forming structures that regulate the selective distribution of ions across the cell membrane or between intracellular compartments. They are fundamental in several physiological processes including cell volume regulation, neurotransmission, and muscle contraction. Therefore, it is not surprising that disruption of ion channel function by genetic mutation can be associated with cardiovascular disorders. KCNH2, also known as the human ether-a-go-go related gene (hERG), encodes the pore-forming subunit of a delayed rectifier voltage-dependent K channel (9). These channels are expressed in numerous cell types, but are most notable for their role in the heart. Normal hERG K channel activity is important for maintaining cardiac electrical activity. The gating properties of hERG K channels makes their contribution ideal for prolonging the duration of the plateau phase (slow activation and rapid inactivation) and for initiating the terminal repolarization phase (rapid recovery from inactivation and slow deactivation) of the action potential. Controlling action potential duration is critical for ensuring sufficient Ca 2 entry to enable cardiac contraction, while the delayed repolarization phase provides some protection against premature contractions (9). Loss-of-function (LOF) mutations can attenuate hERG K channel activity, thus increasing the propensity for the development of life-threatening arrhythmias. For example, LOF mutations in KCNH2 can cause chromosome 7-linked long QT (type 2; LQT2) syndrome, a disorder characterized by abnormal cardiac electrical activity, due to prolongation of the QT interval (2). Although this LOF can be attributed to decreased expression, dominant-negative (DN) effects, or changes in