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Inositol 1,4,5-trisphosphate receptor - reactive oxygen signaling domain regulates excitation-contraction coupling in atrial myocytes. | LitMetric

The inositol 1,4,5-trisphosphate receptor (InsPR) is up-regulated in patients with atrial fibrillation (AF) and InsP-induced Ca release (IICR) is linked to pro-arrhythmic spontaneous Ca release events. Nevertheless, knowledge of the physiological relevance and regulation of InsPRs in atrial muscle is still limited. We hypothesize that InsPR and NADPH oxidase 2 (NOX2) form a functional signaling domain where NOX2 derived reactive oxygen species (ROS) regulate InsPR agonist affinity and thereby Ca release. To quantitate the contribution of IICR to atrial excitation-contraction coupling (ECC) atrial myocytes (AMs) were isolated from wild type and NOX2 deficient (Nox2) mice and changes in the cytoplasmic Ca concentration ([Ca]; fluo-4/AM, indo-1) or ROS (2',7'-dichlorofluorescein, DCF) were monitored by fluorescence microscopy. Superfusion of AMs with Angiotensin II (AngII: 1 μmol/L) significantly increased diastolic [Ca] (F/F, Ctrl: 1.00 ± 0.01, AngII: 1.20 ± 0.03; n = 7; p < 0.05), the field stimulation induced Ca transient (CaT) amplitude (ΔF/F, Ctrl: 2.00 ± 0.17, AngII: 2.39 ± 0.22, n = 7; p < 0.05), and let to the occurrence of spontaneous increases in [Ca]. These changes in [Ca] were suppressed by the InsPR blocker 2-aminoethoxydiphenyl-borate (2-APB; 1 μmol/L). Concomitantly, AngII induced an increase in ROS production that was sensitive to the NOX2 specific inhibitor gp91ds-tat (1 μmol/L). In NOX2 AMs, AngII failed to increase diastolic [Ca], CaT amplitude, and the frequency of spontaneous Ca increases. Furthermore, the enhancement of CaTs by exposure to membrane permeant InsP was abolished by NOX inhibition with apocynin (1 μM). AngII induced IICR in Nox2 AMs could be restored by addition of exogenous ROS (tert-butyl hydroperoxide, tBHP: 5 μmol/L). In saponin permeabilized AMs InsP (5 μmol/L) induced Ca sparks that increased in frequency in the presence of ROS (InsP: 9.65 ± 1.44 sparks*s*(100μm); InsP + tBHP: 10.77 ± 1.5 sparks*s*(100μm); n = 5; p < 0.05). The combined effect of InsP + tBHP was entirely suppressed by 2-APB and Xestospongine C (XeC). Changes in IICR due to InsPR glutathionylation induced by diamide could be reversed by the reducing agent dithiothreitol (DTT: 1 mmol/L) and prevented by pretreatment with 2-APB, supporting that the ROS-dependent post-translational modification of the InsPR plays a role in the regulation of ECC. Our data demonstrate that in AMs the InsPR is under dual control of agonist induced InsP and ROS formation and suggest that InsP and NOX2-derived ROS co-regulate atrial IICR and ECC in a defined InsPR/NOX2 signaling domain.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8826595PMC
http://dx.doi.org/10.1016/j.yjmcc.2021.10.006DOI Listing

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