Pharmacological Approaches for the Modulation of the Potassium Channel K_V4.x and KChIPs

Ion channels are macromolecular complexes present in the plasma membrane and intracellular organelles of cells. Dysfunction of ion channels results in a group of disorders named channelopathies, which represent an extraordinary challenge for study and treatment. In this review, we will focus on voltage-gated potassium channels (K_V), specifically on the K_V4-family. The activation of these channels generates outward currents operating at subthreshold membrane potentials as recorded from myocardial cells (I_TO, transient outward current) and from the somata of hippocampal neurons (I_SA). In the heart, K_V4 dysfunctions are related to Brugada syndrome, atrial fibrillation, hypertrophy, and heart failure. In hippocampus, K_V4.x channelopathies are linked to schizophrenia, epilepsy, and Alzheimer's disease. K_V4.x channels need to assemble with other accessory subunits (β) to fully reproduce the I_TO and I_SA currents. β Subunits affect channel gating and/or the traffic to the plasma membrane, and their dysfunctions may influence channel pharmacology. Among K_V4 regulatory subunits, this review aims to analyze the K_V4/KChIPs interaction and the effect of small molecule KChIP ligands in the A-type currents generated by the modulation of the K_V4/KChIP channel complex. Knowledge gained from structural and functional studies using activators or inhibitors of the potassium current mediated by K_V4/KChIPs will better help understand the underlying mechanism involving K_V4-mediated-channelopathies, establishing the foundations for drug discovery, and hence their treatments.