Pharmacological Approaches for the Modulation of the Potassium Channel K V 4.x and KChIPs

• Published in: International journal of molecular sciences Vol. 22; no. 3
• Main Authors: Cercós, Pilar, Peraza, Diego A, Benito-Bueno, Angela de, Socuéllamos, Paula G, Aziz-Nignan, Abdoul, Arrechaga-Estévez, Dariel, Beato, Escarle, Peña-Acevedo, Emilio, Albert, Armando, González-Vera, Juan A, Rodríguez, Yoel, Martín-Martínez, Mercedes, Valenzuela, Carmen, Gutiérrez-Rodríguez, Marta
• Format: Journal Article
• Language: English
• Published: Switzerland 31.01.2021
• Subjects: potassium channel interacting proteins (KChIPs); protein–protein interactions; KV4/KChIPs modulators; transient outward current; voltage-gated potassium channels KV4; A-type current
• ISSN: 1422-0067

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 ), specifically on the K 4-family. The activation of these channels generates outward currents operating at subthreshold membrane potentials as recorded from myocardial cells (I , transient outward current) and from the somata of hippocampal neurons (I ). In the heart, K 4 dysfunctions are related to Brugada syndrome, atrial fibrillation, hypertrophy, and heart failure. In hippocampus, K 4.x channelopathies are linked to schizophrenia, epilepsy, and Alzheimer's disease. K 4.x channels need to assemble with other accessory subunits (β) to fully reproduce the I and I currents. β Subunits affect channel gating and/or the traffic to the plasma membrane, and their dysfunctions may influence channel pharmacology. Among K 4 regulatory subunits, this review aims to analyze the K 4/KChIPs interaction and the effect of small molecule KChIP ligands in the A-type currents generated by the modulation of the K 4/KChIP channel complex. Knowledge gained from structural and functional studies using activators or inhibitors of the potassium current mediated by K 4/KChIPs will better help understand the underlying mechanism involving K 4-mediated-channelopathies, establishing the foundations for drug discovery, and hence their treatments.