Mondéjar-Parreño, GemaMoreno-Manuel, Ana IRuiz-Robles, Juan ManuelJalife, José2025-06-172025-06-172025-01-10Cell Discov. 2025 Jan 10;11(1):3.https://hdl.handle.net/20.500.12105/26757A well-balanced ion channel trafficking machinery is paramount for the normal electromechanical function of the heart. Ion channel variants and many drugs can alter the cardiac action potential and lead to arrhythmias by interfering with mechanisms like ion channel synthesis, trafficking, gating, permeation, and recycling. A case in point is the Long QT syndrome (LQTS), a highly arrhythmogenic disease characterized by an abnormally prolonged QT interval on ECG produced by variants and drugs that interfere with the action potential. Disruption of ion channel trafficking is one of the main sources of LQTS. We review some molecular pathways and mechanisms involved in cardiac ion channel trafficking. We highlight the importance of channelosomes and other macromolecular complexes in helping to maintain normal cardiac electrical function, and the defects that prolong the QT interval as a consequence of variants or the effect of drugs. We examine the concept of "interactome mapping" and illustrate by example the multiple protein-protein interactions an ion channel may undergo throughout its lifetime. We also comment on how mapping the interactomes of the different cardiac ion channels may help advance research into LQTS and other cardiac diseases. Finally, we discuss how using human induced pluripotent stem cell technology to model ion channel trafficking and its defects may help accelerate drug discovery toward preventing life-threatening arrhythmias. Advancements in understanding ion channel trafficking and channelosome complexities are needed to find novel therapeutic targets, predict drug interactions, and enhance the overall management and treatment of LQTS patients.This work was supported by the National Institutes of Health R01 HL163943; La Caixa Banking Foundation (project code638 LCF/PR/HR19/52160013); grant PI20/01220 of the public call “Proyectos de Investigación en Salud 2020” (PI-FIS-2020) funded by Instituto de Salud Carlos III (ISCIII); MCIU grant BFU2016-75144-R and PID2020-116935RB-I00, and co-founded by Fondo Europeo de Desarrollo Regional (FEDER); and Fundación La Marató de TV3642 (736/C/2020). We also receive support from the European Union’s Horizon 2020 Research and Innovation program (grant agreement GA-965286). A.I.M.M. holds an FPU contract (FPU20/01569) from Ministerio de Universidades and J.M.R. holds an FPU contract (FPU22/03253) from Ministerio de Ciencia, Innovación y Universidades. CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia e Innovación (MCIN) and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (CEX2020-001041-S649 funded by MICIN/AEI/10.13039/501100011033).engVoRhttp://creativecommons.org/licenses/by/4.0/Attribution 4.0 International39788950Cell Discoveryopen access