'Eventless' InsP3‐dependent SR‐Ca2+ release affecting atrial Ca2+ sparks. (4th March 2013)

• Record Type: Journal Article
• Authors: Horn, Tamara; Ullrich, Nina D.; Egger, Marcel
• Is Part Of: Journal of physiology. Volume 591:Number 8(2013:Apr.)
• Page Start: 2103
• Page End: 2111
• Publication Date: 2013-03-04
• Subjects: Physiology -- Periodicals; 612.005
• DOI: 10.1113/jphysiol.2012.247288
• Languages: English
• ISSNs: 0022-3751

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Key points</title> <p> <list id="l1" list-type="simple"> <list-item> <label> </label> <p>Inositol 1, 4, 5‐trisphosphate receptors (InsP<sub>3</sub>Rs) are functionally expressed in cardiac myocytes.</p> </list-item> <list-item> <label> </label> <p>The influence of inositol 1, 4, 5‐trisphosphate‐induced sarcoplasmic reticulum (SR)‐Ca<sup>2+</sup>release (IP3ICR) on atrial excitation‐contraction coupling (ECC) under physiological and pathophysiological conditions remains elusive.</p> </list-item> <list-item> <label> </label> <p>The present study focuses on local IP3ICR and its functional consequences for ryanodine receptor (RyR) activity and subsequent Ca<sup>2+</sup>‐induced Ca<sup>2+</sup> release in atrial myocytes.</p> </list-item> <list-item> <label> </label> <p>Here we show significant SR‐Ca<sup>2+</sup> flux, but eventless SR‐Ca<sup>2+</sup> release through InsP<sub>3</sub>Rs.</p> </list-item> <list-item> <label> </label> <p>We suggest a new mechanism based on eventless and highly efficient InsP<sub>3</sub>‐dependent SR‐Ca<sup>2+</sup> flux as a crucial mechanism of functional cross‐talk between InsP<sub>3</sub>Rs and RyRs, which may be an important factor in the modulation of ECC sensitivity.</p> </list-item> </list> </p> <p> <bold>Abstract </bold> Augmented inositol 1, 4, 5‐trisphosphate receptor (InsP<sub>3</sub>R) function has been linked to a variety of cardiac pathologies, including cardiac arrhythmia. The contribution of inositol 1, 4, 5‐trisphosphate‐induced Ca<sup>2+</sup> release (IP3ICR) in excitation‐contraction coupling (ECC) under physiological conditions, as well as under cellular remodelling, remains controversial. Here we test the hypothesis that local IP3ICR directly affects ryanodine receptor (RyR) function and subsequent Ca<sup>2+</sup>‐induced Ca<sup>2+</sup> release in atrial myocytes. IP3ICR was evoked by UV‐flash photolysis of caged InsP<sub>3</sub> under whole‐cell configuration of the voltage‐clamp technique in atrial myocytes isolated from C57/BL6 mice. Photolytic release of InsP<sub>3</sub> was accompanied by a significant increase in the Ca<sup>2+</sup> release event frequency (4.14 ± 0.72 <italic>vs.</italic> 6.20 ± 0.76 events (100 μm)<sup>−1</sup> s<sup>−1</sup>). These individual photolytically triggered Ca<sup>2+</sup> release events were identified as Ca<sup>2+</sup> sparks, which originated from RyR openings. This was verified by Ca<sup>2+</sup> spark analysis and pharmacological separation between RyR and InsP<sub>3</sub>R‐dependent sarcoplasmic reticulum (SR)‐Ca<sup>2+</sup> release (2‐aminoethoxydiphenyl borate, xestospongin C, tetracaine). Significant SR‐Ca<sup>2+</sup> flux but eventless SR‐Ca<sup>2+</sup> release through InsP<sub>3</sub>R were characterized using SR‐Ca<sup>2+</sup> leak/SR‐Ca<sup>2+</sup> load measurements. These results strongly support the idea that IP3ICR can effectively modulate RyR openings and Ca<sup>2+</sup> spark probability. We conclude that eventless and highly efficient InsP<sub>3</sub>‐dependent SR‐Ca<sup>2+</sup> flux is the main mechanism of functional cross‐talk between InsP<sub>3</sub>Rs and RyRs, which may be an important factor in the modulation of ECC sensitivity.</p> </abstract>