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The p.P888L SAP97 polymorphism increases the transient outward current (I(to,f)) and abbreviates the action potential duration and the QT interval

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...

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Detalles Bibliográficos
Autores principales: Tinaquero, David, Crespo-García, Teresa, Utrilla, Raquel G., Nieto-Marín, Paloma, González-Guerra, Andrés, Rubio-Alarcón, Marcos, Cámara-Checa, Anabel, Dago, María, Matamoros, Marcos, Pérez-Hernández, Marta, Tamargo, María, Cebrián, Jorge, Jalife, José, Tamargo, Juan, Bernal, Juan Antonio, Caballero, Ricardo, Delpón, Eva
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7329876/
https://www.ncbi.nlm.nih.gov/pubmed/32612162
http://dx.doi.org/10.1038/s41598-020-67109-z
Descripción
Sumario: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 (I(to,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 I(to,f), a CaMKII-dependent effect that may increase the risk of arrhythmias.