Potential in targeting classical inward rectifier channels

Abstract

t c Inward rectifier channels were first described in skeletal myocytes as constitutively open potassium-selective channels conducting potassium ions more efficiently in the inward than the outward direction. Later, it was realized that currents with these characteristics are present in many organs, including brain and heart. The diode-like behavior of these channels is based on internal block by Mg and/or polyamines and is crucial for the diverse functions in cell physiologic contexts. Classic inwardly rectifying currents are conducted by a family of Kir2.x proteins. Currently, six Kir2 subunits (Kir2.1–2.6) were described that can assemble to form homomultimeric or heteromultimeric channel complexes. Kir2.1/2.2/2.3 heteromers were suggested to be the structural basis of cardiac channels conducting IK1. IK1 significantly contributes to repolarizing potassium conductance in cardiac late-phase repolarization and stabilizes the resting membrane potential of atrial and ventricular myocytes. Several clinical observations support the concept of an antiarrhythmic effect by Kir2.x modulation and, consequently, small molecule modulators acting on inwardly rectifying K channels were reported as potential promising antiarrhythmic drugs. Kir2.x channel expression and subunit composition change during diverse forms of arrhythmia. Furthermore, overexpression of active or dominant-negative Kir2 channel variants increases the susceptibility of diverse forms of ventricular or atrial arrhythmia, as summarized by van der Heyden and Sanchez-Chapula in their study reported in this issue of eart Rhythm. These data indicate that inwardly rectifying K channels play a key role during development and maintenance of arrhythmias. Therefore, modulation of these channels holds the potential to counteract arrhythmia susceptibility as well. As already described for other antiarrhythmic drugs, inward rectifier targeting compounds most probably will have both proarrhythmic and antiarrhythmic potential. An obvious additional hurdle to overcome in the development of Kir2.x-based antiarrhythmics will be avoiding teratogenic effects, which are suggested by observed impairments such as syndactyly and facial dysmorphia caused by Kir2.1 loss-of-function mutations in Andersen-Tawil syndrome. Therefore, use of these currently