RT Journal Article
T1 The p.P888L SAP97 polymorphism increases the transient outward current (Ito,f) and abbreviates the action potential duration and the QT interval
A1 Tinaquero, David
A1 Crespo García, María Teresa
A1 García Utrilla, Raquel
A1 Nieto Marín, Paloma
A1 Nieto Marín, Paloma
A1 Rubio Alarcón, Marcos
A1 Cámara Checa, Anabel
A1 Dago Requena, María
A1 Matamoros Campos, Marcos
A1 Cebrián Castillo, Jorge
A1 Tamargo Menéndez, Juan
A1 Caballero Collado, Ricardo
A1 Delpón Mosquera, María Eva
AB Synapse-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.
PB Nature Research
SN 2045-2322
YR 2020
FD 2020-07-01
LK https://hdl.handle.net/20.500.14352/93988
UL https://hdl.handle.net/20.500.14352/93988
LA eng
NO Tinaquero, 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-z
NO Ministerio de Economía y Competitividad
NO Comunidad Autónoma de Madrid
NO Universidad Complutense de Madrid
NO European Structural and Investment Funds
NO Instituto de Salud Carlos III
NO Sociedad Española de Cardiología
DS Docta Complutense
RD 9 abr 2025