Size matters: Ryanodine receptor cluster size affects arrhythmogenic sarcoplasmic reticulum calcium release

Samuel Galice, Yuanfang Xie, Yi Yang, Daisuke Sato, Donald M Bers

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

Background-Ryanodine receptors (RyR) mediate sarcoplasmic reticulum calcium (Ca2+) release and influence myocyte Ca2+ homeostasis and arrhythmias. In cardiac myocytes, RyRs are found in clusters of various sizes and shapes, and RyR cluster size may critically influence normal and arrhythmogenic Ca2+ spark and wave formation. However, the actual RyR cluster sizes at specific Ca2+ spark sites have never been measured in the physiological setting. Methods and Results-Here we measured RyR cluster size and Ca2+ sparks simultaneously to assess how RyR cluster size influences Ca2+ sparks and sarcoplasmic reticulum Ca2+ leak. For small RyR cluster sizes (<50), Ca2+ spark frequency is very low but then increases dramatically at larger cluster sizes. In contrast, Ca2+ spark amplitude is nearly maximal even at relatively small RyR cluster size (≈10) and changes little at larger cluster size. These properties agreed with computational simulations of RyR gating within clusters. Conclusions-Our study explains how this combination of properties may limit arrhythmogenic Ca2+ sparks and wave propagation (at many junctions) while preserving the efficacy and spatial synchronization of Ca2+-induced Ca2+-release during normal excitation-contraction coupling. However, variations in RyR cluster size among individual junctions and RyR sensitivity could exacerbate heterogeneity of local sarcoplasmic reticulum Ca2+ release and arrhythmogenesis under pathological conditions.

Original languageEnglish (US)
Article numbere008724
JournalJournal of the American Heart Association
Volume7
Issue number13
DOIs
StatePublished - Jul 1 2018

Keywords

  • Calcium regulation
  • Calcium signaling
  • Calcium sparks
  • Ryanodine receptor

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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