2022
Basic Research in Cardiology

InsP3R-RyR Ca2+ channel crosstalk facilitates arrhythmias in the failing human ventricle

Authors:

Xin Jin, Matthew Amoni, Guillaume Gilbert, Eef Dries, Rosa Doñate Puertas, Ashutosh Tomar, Chandan K Nagaraju, Ankit Pradhan, David I Yule, Tobie Martens, Roxane Menten, Pieter Vanden Berghe, Filip Rega, Karin Sipido, H Llewelyn Roderick

Keywords:

Human ventricle, Arrhythmia

Abstract:

Dysregulated intracellular Ca²⁺ handling involving altered Ca²⁺ release from intracellular stores via RyR channels underlies both arrhythmias and reduced function in heart failure (HF). Mechanisms linking RyR dysregulation and disease are not fully established. Studies in animals support a role for InsP₃ receptor Ca²⁺ channels (InsP₃R) in pathological alterations in cardiomyocyte Ca²⁺ handling but whether these findings translate to the divergent physiology of human cardiomyocytes during heart failure is not determined. Using electrophysiological and Ca²⁺ recordings in human ventricular cardiomyocytes, we uncovered that Ca²⁺ release via InsP₃Rs facilitated Ca²⁺ release from RyR and induced arrhythmogenic delayed after depolarisations and action potentials. InsP₃R-RyR crosstalk was particularly increased in HF at RyR clusters isolated from the T-tubular network. Reduced SERCA activity in HF further facilitated the action of InsP₃. Nanoscale imaging revealed co-localisation of InsP₃Rs with RyRs in the dyad, which was increased in HF, providing a mechanism for augmented Ca²⁺ channel crosstalk. Notably, arrhythmogenic activity dependent on InsP₃Rs was increased in tissue wedges from failing hearts perfused with AngII to promote InsP₃ generation. These data indicate a central role for InsP₃R-RyR Ca²⁺ signalling crosstalk in the pro-arrhythmic action of GPCR agonists elevated in HF and the potential for their therapeutic targeting.