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

Ingrid M Bonilla,Sandor Gyorke,Noah Weisleder,Silvia Priori,Galina Sakuta,Cynthia A Carnes,Tom Bodnar,Rengasayee Veeraraghavan,Przemysław B Radwański,Andrei Stepanov,Pompeo Volpe,Bin Liu,Andriy E Belevych,Louisa Mezache,Stephen Baine

doi:10.1038/s41598-019-46427-x

Abstract

Store-operated Ca2+ entry (SOCE), a major Ca2+ signaling mechanism in non-myocyte cells, has recently emerged as a component of Ca2+ 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 local, transient Ca2+entry (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 Ca2+ 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.

Highlights

We examined the compartmentalization of Store-operated Ca2+ entry (SOCE) in ventricular myocytes derived from WT mice and mice affected by catecholaminergic polymorphic ventricular tachycardia (CPVT) using a combination of functional live cell (2D resonant-scanning confocal Ca2+ imaging) and molecular visualization
Redistribution of STIM1 and ORAI1 from interior regions to the intercalated disk (ID) resulted in augmented SOCE in myocytes from arrhythmia-prone (CPVT) hearts
We provide novel insights into the functional properties, and molecular underpinnings of SOCE in the adult cardiac myocyte

Summary

Introduction

A growing body of evidence links pathological enhancement of SOCE to cardiac disease[6,8]. It remains unclear whether and how cardiac SOCE contributes to physiological or pathological intracellular signaling in the presence of much larger Ca2+ fluxes involved in canonical ECC. Our data suggest a novel arrhythmia mechanism in CPVT driven by pathological remodeling of SOCE machinery, and consequent enhancement of SOCE. Taken together, these results provide much- needed insights into the nature and roles of SOCE in the normal and diseased heart, and as a potential target for anti-arrhythmia therapy

Methods

Results

Conclusion