Pharmacological Approaches for the Modulation of the Potassium Channel K(V)4.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(V)4-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(V)4 dysfunctions are related to Brugada syndrome, atrial fibrillation, hypertrophy, and heart failure. In hippocampus, K(V)4.x channelopathies are linked to schizophrenia, epilepsy, and Alzheimer’s disease. K(V)4.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(V)4 regulatory subunits, this review aims to analyze the K(V)4/KChIPs interaction and the effect of small molecule KChIP ligands in the A-type currents generated by the modulation of the K(V)4/KChIP channel complex. Knowledge gained from structural and functional studies using activators or inhibitors of the potassium current mediated by K(V)4/KChIPs will better help understand the underlying mechanism involving K(V)4-mediated-channelopathies, establishing the foundations for drug discovery, and hence their treatments.