Pharmacological Approaches for the Modulation of the Potassium Channel KV4.x and KChIPs
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Voltage-gated potassium channels KV4Transient outward currentA-type currentPotassium channel interacting proteins (KChIPs)Protein–protein interactions
Cercós, P.; Peraza, D.A.; Benito-Bueno, A.d.; Socuéllamos, P.G.; Aziz-Nignan, A.; Arrechaga-Estévez, D.; Beato, E.; Peña-Acevedo, E.; Albert, A.; González-Vera, J.A.; et al. Pharmacological Approaches for the Modulation of the Potassium Channel KV4.x and KChIPs. Int. J. Mol. Sci. 2021, 22, 1419. https://doi.org/ 10.3390/ijms22031419
SponsorshipMinisterio de Ciencia e Innovacion (MICIU) Spain SAF201675021-R PID2019-104366RB-C21 RTI2018-097189-B-C22 PID2019-104366RBC22; Instituto de Salud Carlos III CIBERCV program CB/11/00222; Consejo Superior de Investigaciones Cientificas (CSIC) PIE 201820E104 2019AEP148 201880E109; European Fund for Economic and Regional Development (FEDER); Spanish Ministry of Economy, Industry, and Competitivity (MINECO); Consejo Superior de Investigaciones Cientificas (CSIC) BES-2017-080184 FPU2017/02731; Department of Atomic Energy (DAE); CUNY Research Scholars Program; Collegiate Science Technology Entry Program (CSTEP); Hostos Office of Academic Affairs; CSIC Open Access Publication Support Initiative through its Unit of Information Resources for Research (URICI)
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 (KV), specifically on the KV4-family. The activation of these channels generates outward currents operating at subthreshold membrane potentials as recorded from myocardial cells (ITO, transient outward current) and from the somata of hippocampal neurons (ISA). In the heart, KV4 dysfunctions are related to Brugada syndrome, atrial fibrillation, hypertrophy, and heart failure. In hippocampus, KV4.x channelopathies are linked to schizophrenia, epilepsy, and Alzheimer’s disease. KV4.x channels need to assemble with other accessory subunits (β) to fully reproduce the ITO and ISA currents. β Subunits affect channel gating and/or the traffic to the plasma membrane, and their dysfunctions may influence channel pharmacology. Among KV4 regulatory subunits, this review aims to analyze the KV4/KChIPs interaction and the effect of small molecule KChIP ligands in the A-type currents generated by the modulation of the KV4/KChIP channel complex. Knowledge gained from structural and functional studies using activators or inhibitors of the potassium current mediated by KV4/KChIPs will better help understand the underlying mechanism involving KV4-mediated-channelopathies, establishing the foundations for drug discovery, and hence their treatments.