1. The p.P888L SAP97 polymorphism increases the transient outward current (I to,f ) and abbreviates the action potential duration and the QT interval.
- Author
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Tinaquero D, Crespo-García T, Utrilla RG, Nieto-Marín P, González-Guerra A, Rubio-Alarcón M, Cámara-Checa A, Dago M, Matamoros M, Pérez-Hernández M, Tamargo M, Cebrián J, Jalife J, Tamargo J, Bernal JA, Caballero R, and Delpón E
- Subjects
- Animals, Arrhythmias, Cardiac genetics, CHO Cells, Calcium-Calmodulin-Dependent Protein Kinase Type 2 genetics, Cell Line, Cricetulus, Discs Large Homolog 1 Protein genetics, Humans, Kv1.5 Potassium Channel physiology, Mice, Patch-Clamp Techniques, Phosphorylation physiology, Polymorphism, Single Nucleotide genetics, Action Potentials physiology, Arrhythmias, Cardiac physiopathology, Calcium-Calmodulin-Dependent Protein Kinase Type 2 physiology, Discs Large Homolog 1 Protein metabolism, Myocytes, Cardiac metabolism, Shal Potassium Channels physiology
- Abstract
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.- Published
- 2020
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