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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.

Pharmacological Approaches for the Modulation of the Potassium Channel KV4.x and KChIPs