Enhancement of Cardiac Store Operated Calcium Entry (SOCE) within Novel Intercalated Disk Microdomains in Arrhythmic Disease

Abstract

Store-operated Ca 2+ entry (SOCE), a major Ca 2+ signaling mechanism in non-myocyte cells, has recently emerged as a component of Ca 2+ signaling in cardiac myocytes. Though it has been reported to play a role in cardiac arrhythmias and to be upregulated in cardiac disease, little is known about the fundamental properties of cardiac SOCE, its structural underpinnings or effector targets. An even greater question is how SOCE interacts with canonical excitation-contraction coupling (ECC). We undertook a multiscale structural and functional investigation of SOCE in cardiac myocytes from healthy mice (wild type; WT) and from a genetic murine model of arrhythmic disease (catecholaminergic ventricular tachycardia; CPVT). Here we provide the first demonstration of lo cal, transient C a 2+ e ntry (LoCE) events, which comprise cardiac SOCE. Although infrequent in WT myocytes, LoCEs occurred with greater frequency and amplitude in CPVT myocytes. CPVT myocytes also evidenced characteristic arrhythmogenic spontaneous Ca 2+ waves under cholinergic stress, which were effectively prevented by SOCE inhibition. In a surprising finding, we report that both LoCEs and their underlying protein machinery are concentrated at the intercalated disk (ID). Therefore, localization of cardiac SOCE in the ID compartment has important implications for SOCE-mediated signaling, arrhythmogenesis and intercellular mechanical and electrical coupling in health and disease.

The mitochondrial K-ATP channel opener diazoxide upregulates STIM1 and Orai1 via ROS and the MAPK pathway in adult rat cardiomyocytes

“…1g). In adult cardiomyocytes Orai1 does not follow the striated pattern of STIM1 distribution [21] as we also observed in control experiments. In Dzx-treated cardiomyocytes we found that Orai1 also was expressed along the surface membrane albeit at much greater levels ( Fig.…”

“…Notably, although Dzx increased STIM1 expression, it completely disrupted its striated distribution pattern in cardiomyocytes. Interestingly, the localization of STIM1 resembles the distribution of the junctional sarcoplasmic reticulum along the Z-disk [7]. We con rmed this distribution in control experiments wherein peaks of uorescence were observed to be evenly distributed along the longitudinal axis, separated by distances consistent with sarcomere length.…”

ER stress increases store-operated Ca2+ entry (SOCE) and augments basal insulin secretion in pancreatic beta cells

“…Removing extracellular Ca 2+ confirmed the results we obtained with YM, supporting the hypothesis that the oscillations seen after TM treatment indeed require increased influx of extracellular Ca 2+ ( Figure S1A). On the other hand, applying other SOCE channel blockers, 2-Aminoethoxydiphenyl borate (2APB) or SKF96365 (SKF) acutely at the end of a Ca 2+ imaging experiment surprisingly increased cytosolic Ca 2+ levels in both control and experimental groups ( Figure S1B and S1C) (64,65). 2APB and SKF are nonselective SOCE inhibitors as they also inhibit other channels over a similar concentration range (66).…”

Specific Upregulation of TRPC1 and TRPC5 Channels by Mineralocorticoid Pathway in Adult Rat Ventricular Cardiomyocytes

“…However, these conditions might not sufficiently deplete the SR Ca 2+ stores of quiescent adult ventricular cells [15,46], even if one might think that, in the presence of an SERCA pump inhibitor, the SR Ca 2+ leak would deplete the SR [45]. Thus, when a clear SR Ca 2+ depletion is observed (with ryanodine receptor activation through either stimulation or caffeine/ryanodine application), a moderated SOCE activity might be observed [11,14,[47][48][49], as we show in the present study.…”