Inhibition of Cardiac Inward Rectifier Currents by Cationic Amphiphilic Drugs

M.   A.G. van der   Heyden; A.      Stary-Weinzinger; J.   A.   Sanchez-Chapula

doi:10.2174/15665240113139990043

Abstract

Cardiac inward rectifier channels belong to three different classes of the K_IR channel protein family. The K_IR2.x proteins generate the classical inward rectifier current, I_K1, while K_IR3 and KL_IR6 members are responsible for the acetylcholine responsive and ATP sensitive inward rectifier currents I_KAch and I_KATP, respectively. Aberrant function of these channels has been correlated with severe cardiac arrhythmias, indicating their significant contribution to normal cardiac electrophysiology. A common feature of inward rectifier channels is their dependence on the lipid phosphatidyl-4,5-bisphospate (PIP2) interaction for functional activity. Cationic amphiphilic drugs (CADs) are one of the largest classes of pharmaceutical compounds. Several widely used CADs have been associated with inward rectifier current disturbances, and recent evidence points to interference of the channel-PIP₂ interaction as the underlying mechanism of action. Here, we will review how six of these well known drugs, used for treatment in various different conditions, interfere in cardiac inward rectifier functioning. In contrast, K_IR channel inhibition by the anionic anesthetic thiopental is achieved by a different mechanism of channel-PIP₂ interference. We will discuss the latest basic science insights of functional inward rectifier current characteristics, recently derived K_IR channel structures and specific PIP₂-receptor interactions at the molecular level and provide insight in how these drugs interfere in the structure-function relationships.