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


RESULTS
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.


CONCLUSIONS
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.
Marcel
M
Wullschleger
Joaquim
J
Blanch
Marcel
M
Egger
D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects; D004558:Electric Stimulation; D019332:Endothelin-1 / Q000494:pharmacology; D006325:Heart Atria / Q000378:metabolism; D007091:Image Processing, Computer-Assisted; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D010641:Phenotype; D020239:Receptor Cross-Talk / Q000187:drug effects; D019837:Ryanodine Receptor Calcium Release Channel / Q000187:drug effects / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D013997:Time Factors
D019332:Endothelin-1; D053496:Inositol 1,4,5-Trisphosphate Receptors; C580990:Ip3r2 protein, mouse; D019837:Ryanodine Receptor Calcium Release Channel; C000592748:ryanodine receptor 2. mouse; D015544:Inositol 1,4,5-Trisphosphate
Atrial myocytes; CICR; Ca2+ puffs; Ca2+ sparks; InsP3R; Local modulation of calcium sparks and calcium puffs; RyR