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, Peter Lipp

Research output: Contribution to journalArticlepeer-review

195 Scopus citations


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 β-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 β-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-amino-ethoxydiphenyl 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.

Original languageEnglish (US)
Pages (from-to)395-409
Number of pages15
JournalJournal of Physiology
Issue number2
StatePublished - Jun 1 2002

ASJC Scopus subject areas

  • Physiology


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