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The role of inositol 1,4,5-trisphosphate receptors in Ca²⁺ signalling and the generation of arrhythmias in rat atrial myocytes

Lauren Mackenzie *, Martin D. Bootman *†, Mika Laine *‡, Michael J. Berridge *, Jan Thuring †, Andrew Holmes †, Wen-Hong Li § and Peter Lipp *

Various cardio-active stimuli, including endothelin-1 (ET-1), exhibit potent arrhythmogenicity, but the underlying cellular mechanisms of their actions are largely unclear. We used isolated rat atrial myocytes and related changes in their subcellular Ca²⁺ signalling to the ability of various stimuli to induce diastolic, premature extra Ca²⁺ transients (ECTs). For this, we recorded global and spatially resolved Ca²⁺ signals in indo-1- and fluo-4-loaded atrial myocytes during electrical pacing. ET-1 exhibited a higher arrhythmogenicity (arrhythmogenic index; ratio of number of ECTs over fold-increase in Ca²⁺ response, 8.60; n = 8 cells) when compared with concentrations of cardiac glycosides (arrhythmogenic index, 4.10; n = 8 cells) or the -adrenergic agonist isoproterenol (arrhythmogenic index, 0.11; n = 6 cells) that gave similar increases in the global Ca²⁺ responses. Seventy-five percent of the ET-1-induced arrhythmogenic Ca²⁺ transients were accompanied by premature action potentials, while for digoxin this proportion was 25 %. The -adrenergic agonist failed to elicit a significant number of ECTs. Direct activation of inositol 1,4,5-trisphosphate (InsP₃) receptors with a membrane-permeable InsP₃ ester (InsP₃ BM) mimicked the effect of ET-1 (arrhythmogenic index, 14.70; n = 6 cells). Inhibition of InsP₃ receptors using 2 µM 2-aminoethoxydiphenyl borate, which did not display any effects on Ca²⁺ signalling under control conditions, specifically suppressed the arrhythmogenic action of ET-1 and InsP₃ BM. Immunocytochemistry indicated a co-localisation of peripheral, junctional ryanodine receptors with InsP₃Rs. Thus, the pronounced arrhythmogenic potency of ET-1 is due to the spatially specific recruitment of Ca²⁺ sparks by subsarcolemmal InsP₃Rs. Summation of such sparks efficiently generates delayed afterdepolarisations that trigger premature action potentials. We conclude that the particular spatial profile of cellular Ca²⁺ signals is a major, previously unrecognised, determinant for arrhythmogenic potency and that the InsP₃ signalling cassette might therefore be a promising new target for understanding and managing atrial arrhythmia.

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