{"authors":[{"id":null,"fullName":"Gema Mondéjar-Parreño","name":"Gema","surname":"Mondéjar-Parreño","rank":1,"pid":{"id":{"scheme":"orcid_pending","value":"0000-0001-9514-8961"},"provenance":null}},{"id":"orcid_______::32b50760e1f40291d77e9775102efbbd","fullName":"Ana I. 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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 <jats:italic>channelosomes</jats:italic> 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 <jats:italic>channelosome</jats:italic> complexities are needed to find novel therapeutic targets, predict drug interactions, and enhance the overall management and treatment of LQTS patients.</jats:p>"],"publicationDate":"2025-01-10","publisher":"Springer Science and Business Media LLC","embargoEndDate":null,"sources":["Crossref","Cell Discov","reponame:Repisalud","instname:Instituto de Salud Carlos III (ISCIII)","Cell Discovery, Vol 11, Iss 1, Pp 1-26 (2025)"],"formats":["application/pdf"],"contributors":["National Institutes of Health (Estados Unidos)","Fundación La Caixa","Instituto de Salud Carlos III","Ministerio de Ciencia, Innovación y Universidades (España)","Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF)","Fundación La Marató TV3","Ministerio de Universidades (España)","Ministerio de Ciencia e Innovación (España)","Fundación ProCNIC","Ministerio de Ciencia e Innovación. 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The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. 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