RyR2R420Q catecholaminergic polymorphic ventricular tachycardia mutation induces bradycardia by disturbing the coupled clock pacemaker mechanism
| Autor: | Wang, YY, Mesirca, P, Marques-Sule, E, Zahradnikova, A, Villejoubert, O, D'Ocon, P, Ruiz, C, Domingo, D, Zorio, E, Mangoni, ME, Benitah, JP, Gomez, AM |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: | |
| Zdroj: | Jci Insight r-IIS La Fe. Repositorio Institucional de Producción Científica del Instituto de Investigación Sanitaria La Fe instname |
| ISSN: | 2379-3708 |
| Popis: | Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a lethal genetic arrhythmia that manifests syncope or sudden death in children and young adults under stress conditions. CPVT patients often present bradycardia and sino-atrial node (SAN) dysfunction. However, the mechanism remains unclear. We analyzed SAN function in two CPVT families and in a novel knockin (KI) mouse model carrying the RyR(2)(R420Q) mutation. Humans and KI mice presented slower resting heart rate. Accordingly, the rate of spontaneous intracellular Ca2+ ([Ca2+] i) transients was slower in KI mouse SAN preparations than in WT, without any significant alteration in the "funny" current (I-f). The L-type Ca2+ current was reduced in KI SAN cells in a [Ca2+](i)-dependent way, suggesting that bradycardia was due to disrupted crosstalk between the "voltage" and "Ca2+" clock, and the mechanisms of pacemaking was induced by aberrant spontaneous RyR(2)-dependent Ca2+ release. This finding was consistent with a higher Ca2+ leak during diastolic periods produced by long-lasting Ca2+ sparks in KI SAN cells. Our results uncover a mechanism for the CPVT-causing RyR(2) N-terminal mutation R420Q, and they highlight the fact that enhancing the Ca2+ clock may slow the heart rhythm by disturbing the coupling between Ca2+ and voltage clocks. |
| Databáze: | OpenAIRE |
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