Inositol 1,4,5-trisphosphate-mediated sarcoplasmic reticulum-mitochondrial crosstalk influences adenosine triphosphate production via mitochondrial Ca2+ uptake through the mitochondrial ryanodine receptor in cardiac myocytes.

Elevated levels of inositol 1,4,5-trisphosphate (IP3) in adult cardiac myocytes are typically associated with the development of cardiac hypertrophy, arrhythmias, and heart failure. IP3 enhances intracellular Ca(2+ )release via IP3 receptors (IP3Rs) located at the sarcoplasmic reticulum (SR). We aimed to determine whether IP3-induced Ca(2+ )release affects mitochondrial function and determine the underlying mechanisms. We compared the effects of IP3Rs- and ryanodine receptors (RyRs)-mediated cytosolic Ca(2+ )elevation achieved by endothelin-1 (ET-1) and isoproterenol (ISO) stimulation, respectively, on mitochondrial Ca(2+ )uptake and adenosine triphosphate (ATP) generation. Both ET-1 and isoproterenol induced an increase in mitochondrial Ca(2+ )(Ca(2 +) m) but only ET-1 led to an increase in ATP concentration. ET-1-induced effects were prevented by cell treatment with the IP3 antagonist 2-aminoethoxydiphenyl borate and absent in myocytes from transgenic mice expressing an IP3 chelating protein (IP3 sponge). Furthermore, ET-1-induced mitochondrial Ca(2+) uptake was insensitive to the mitochondrial Ca(2+ )uniporter inhibitor Ru360, however was attenuated by RyRs type 1 inhibitor dantrolene. Using real-time polymerase chain reaction, we detected the presence of all three isoforms of IP3Rs and RyRs in murine ventricular myocytes with a dominant presence of type 2 isoform for both receptors. Stimulation of IP3Rs with ET-1 induces Ca(2+ )release from the SR which is tunnelled to mitochondria via mitochondrial RyR leading to stimulation of mitochondrial ATP production.

Seidlmayer LK ，Kuhn J ，Berbner A ，Arias-Loza PA ，Williams T ，Kaspar M ，Czolbe M ，Kwong JQ ，Molkentin JD ，Heinze KG ，Dedkova EN ，Ritter O ... -  《-》

Obstruction of ventricular Ca(2+) -dependent arrhythmogenicity by inositol 1,4,5-trisphosphate-triggered sarcoplasmic reticulum Ca(2+) release.

Augmented inositol 1,4,5-trisphosphate (IP3 ) receptor (IP3 R2) expression has been linked to a variety of cardiac pathologies. Although cardiac IP3 R2 function has been in the focus of research for some time, a detailed understanding of its potential role in ventricular myocyte excitation-contraction coupling under pathophysiological conditions remains elusive. The present study focuses on mechanisms of IP3 R2-mediated sarcoplasmic reticulum (SR)-Ca2+ release in ventricular excitation-contraction coupling under IP3 R2-overexpressing conditions by studying intracellular Ca2+ events. We report that, upon IP3 R2 overexpression in ventricular myocytes, IP3 -induced Ca2+ release (IP3 ICR) modulates the SR-Ca2+ content via "eventless" SR-Ca2+ release, affecting the global SR-Ca2+ leak. Thus, IP3 R2 activation could act as a SR-Ca2+ gateway mechanism to escape ominous SR-Ca2+ overload. Our approach unmasks a so far unrecognized mechanism by which "eventless" IP3 ICR plays a protective role against ventricular Ca2+ -dependent arrhythmogenicity. Augmented inositol 1,4,5-trisphosphate (IP3 ) receptor (IP3 R2) function has been linked to a variety of cardiac pathologies including cardiac arrhythmias. The functional role of IP3 -induced Ca2+ release (IP3 ICR) within ventricular excitation-contraction coupling (ECC) remains elusive. As part of pathophysiological cellular remodelling, IP3 R2s are overexpressed and have been repeatedly linked to enhanced Ca2+ -dependent arrhythmogenicity. In this study we test the hypothesis that an opposite scenario might be plausible in which IP3 ICR is part of an ECC protecting mechanism, resulting in a Ca2+ -dependent anti-arrhythmogenic response on the cellular scale. IP3 R2 activation was triggered via endothelin-1 or IP3 -salt application in single ventricular myocytes from a cardiac-specific IP3 R type 2 overexpressing mouse model. Upon IP3 R2 overexpression, IP3 R activation reduced Ca2+ -wave occurrence (46 vs. 21.72%; P < 0.001) while its block increased SR-Ca2+ content (∼29.4% 2-aminoethoxydiphenyl borate, ∼16.4% xestospongin C; P < 0.001), suggesting an active role of IP3 ICR in SR-Ca2+ content regulation and anti-arrhythmogenic function. Pharmacological separation of ryanodine receptor RyR2 and IP3 R2 functions and two-dimensional Ca2+ event analysis failed to identify local IP3 ICR events (Ca2+ puffs). SR-Ca2+ leak measurements revealed that under pathophysiological conditions, "eventless" SR-Ca2+ efflux via enhanced IP3 ICR maintains the SR-Ca2+ content below Ca2+ spark threshold, preventing aberrant SR-Ca2+ release and resulting in a protective mechanism against SR-Ca2+ overload and arrhythmias. Our results support a so far unrecognized modulatory mechanism in ventricular myocytes working in an anti-arrhythmogenic fashion.

Blanch I Salvador J ，Egger M 《-》

Functional local crosstalk of inositol 1,4,5-trisphosphate receptor- and ryanodine receptor-dependent Ca2+ release in atrial cardiomyocytes.

Enhanced inositol 1,4,5-trisphosphate receptor (InsP3R2) expression has been associated with a variety of proarrhythmogenic cardiac disorders. The functional interaction between the two major Ca2+ release mechanisms in cardiomyocytes, Ca2+ release mediated by ryanodine receptors (RyR2s) and InsP3-induced intracellular Ca2+ release (IP3ICR) remains enigmatic. We aimed at identifying characterizing local IP3ICR events, and elucidating functional local crosstalk mechanisms between cardiac InsP3R2s and RyR2s under conditions of enhanced cardiac specific InsP3R2 activity. Using confocal imaging and two-dimensional spark analysis, we demonstrate in atrial myocytes (mouse model cardiac specific overexpressing InsP3R2s) that local Ca2+ release through InsP3Rs (Ca2+ puff) directly activates RyRs and triggers elementary Ca2+ release events (Ca2+ sparks). In the presence of increased intracellular InsP3 concentrations IP3ICR can modulate RyRs openings and Ca2+ spark probability. We show as well that IP3ICR remains under local control of Ca2+ release through RyRs. Our results support the concept of bidirectional interaction between RyRs and InsP3Rs (i.e. Ca2+ sparks and Ca2+ puffs) in atrial myocytes. We conclude that highly efficient InsP3 dependent SR-Ca2+ flux constitute the main mechanism of functional crosstalk between InsP3Rs and RyRs resulting in more Ca2+ sensitized RyRs to trigger subsequent Ca2+-induced Ca2+ release activation. In this way, bidirectional local interaction of both SR-Ca2+ release channels may contribute to the shaping of global Ca2+ transients and thereby to contractility in cardiac myocytes.

Wullschleger M ，Blanch J ，Egger M 《-》

Diverse regulation of IP3 and ryanodine receptors by pentazocine through σ1-receptor in cardiomyocytes.

Tagashira H ，Bhuiyan MS ，Fukunaga K 《-》

Ca2+ responses of pulmonary arterial myocytes to acute hypoxia require release from ryanodine and inositol trisphosphate receptors in sarcoplasmic reticulum.

Wang J ，Shimoda LA ，Sylvester JT 《-》