Tinaquero, DavidCrespo García, María TeresaGarcía Utrilla, RaquelNieto Marín, PalomaNieto Marín, PalomaRubio Alarcón, MarcosCámara Checa, AnabelDago Requena, MaríaMatamoros Campos, MarcosCebrián Castillo, JorgeTamargo Menéndez, JuanCaballero Collado, RicardoDelpón Mosquera, María Eva2024-01-192024-01-192020-07-01Tinaquero, D., Crespo-García, T., Utrilla, R.G. et al. The p.P888L SAP97 polymorphism increases the transient outward current (Ito,f) and abbreviates the action potential duration and the QT interval. Sci Rep 10, 10707 (2020). https://doi.org/10.1038/s41598-020-67109-z2045-232210.1038/s41598-020-67109-zhttps://hdl.handle.net/20.500.14352/93988Synapse-Associated Protein 97 (SAP97) is an anchoring protein that in cardiomyocytes targets to the membrane and regulates Na+ and K+ channels. Here we compared the electrophysiological effects of native (WT) and p.P888L SAP97, a common polymorphism. Currents were recorded in cardiomyocytes from mice trans-expressing human WT or p.P888L SAP97 and in Chinese hamster ovary (CHO)-transfected cells. The duration of the action potentials and the QT interval were significantly shorter in p.P888L-SAP97 than in WT-SAP97 mice. Compared to WT, p.P888L SAP97 significantly increased the charge of the Ca-independent transient outward (Ito,f) current in cardiomyocytes and the charge crossing Kv4.3 channels in CHO cells by slowing Kv4.3 inactivation kinetics. Silencing or inhibiting Ca/calmodulin kinase II (CaMKII) abolished the p.P888L-induced Kv4.3 charge increase, which was also precluded in channels (p.S550A Kv4.3) in which the CaMKII-phosphorylation is prevented. Computational protein-protein docking predicted that p.P888L SAP97 is more likely to form a complex with CaMKII than WT. The Na+ current and the current generated by Kv1.5 channels increased similarly in WT-SAP97 and p.P888L-SAP97 cardiomyocytes, while the inward rectifier current increased in WT-SAP97 but not in p.P888L-SAP97 cardiomyocytes. The p.P888L SAP97 polymorphism increases the Ito,f, a CaMKII-dependent effect that may increase the risk of arrhythmias.engAttribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/journal articlehttps://www.nature.com/articles/s41598-020-67109-z#article-infohttps://www.nature.com/srep/open access615.01/.03Ciencias Biomédicas32 Ciencias Médicas