Abstract
Inositol-1,4,5-trisphosphate (IP3) is a second messenger produced upon agonist binding to a G-protein coupled receptor (GPCR) and subsequently triggers SR-Ca2+ release through openings of IP3 receptors (IP3Rs). In cardiac muscle, IP3R type 2 (IP3R2) is the predominant isoform expressed both in ventricle and atrial tissue. Several studies have focused on the functional interaction between ryanodine receptors (RyRs) and IP3Rs in atrial myocytes. However, it is still unclear how IP3-induced Ca2+ release (IP3ICR) may contribute to excitation-contraction coupling in ventricle. Evidence suggests that IP3ICR modulates the RyR function by affecting its local Ca2+ environment. Under pathophysiological cellular remodeling conditions (e.g. atrial fibrillation and heart failure) a functional interplay of IP3R and RyR Ca2+ events may be significantly pronounced. Our aim in this study was to examine this interaction in a cardiac-specific IP3R2 overexpressing (TG) mouse model. Our experimental approach includes: characterization of the IP3 signaling pathway by various pharmacological interventions; electrophysiology under whole-cell configuration of the patch clamp technique in combination with rapid confocal Ca2+ imaging and complemented with molecular biology approaches (RT-PCR, Western Blot, immunostaining). Western blot results show an increase in IP3R2 protein expression in the TG model both in atria and ventricular tissue compared to its wild-type littermate (FVB). However, a similar distribution on the junctional SR was found, where IP3Rs co-localize with RyRs. Supporting the protein data, preliminary results show an increase in basal spark frequency (SpF) in TG atrial and ventricular myocytes compared to FVB. Upon IP3 stimulation FVB atrial and ventricular cardiomyocytes presented an increase in SpF. Furthermore, a larger increment was seen in TG atrial myocytes. In order to examine the contribution of the SR-Ca2+ leak mediated by IP3R2 a SR-Ca2+ leak protocol was established. However, even under control conditions a significant contribution of IP3ICR on the SR-Ca2+ leak was found. We conclude that overexpression of IP3R2 in the TG model affects Ca2+ handling significantly by functional interplay with the RyR2.
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