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Front. Physiol. | doi: 10.3389/fphys.2018.01379

The Histidine-Rich Calcium Binding Protein in Regulation of Cardiac Rhythmicity

  • 1Biomedical Research Foundation of the Academy of Athens, Greece
  • 2Department of Cardiothoracic Surgery, Cardiovascular Research Institute Maastricht, Maastricht University, Netherlands
  • 3Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, United States
  • 44th Department of Internal Medicine, Attikon Hospital, National and Kapodistrian University of Athens, Greece

Sudden unexpected cardiac death (SCD) accounts for up to half of all-cause mortality of heart failure patients. Standardized cardiology tools such as electrocardiography, cardiac imaging, electrophysiological and serum biomarkers cannot accurately predict which patients are at risk of life-threatening arrhythmic episodes. Recently, a common variant of the histidine-rich calcium binding protein (HRC), the Ser96Ala, was identified as a potent biomarker of malignant arrhythmia triggering in these patients. HRC has been shown to be involved in the regulation of cardiac sarcoplasmic reticulum (SR) Ca2+ cycling, by binding and storing Ca2+ in the SR, as well as interacting with the SR Ca2+ uptake and release complexes. The underlying mechanisms, elucidated by studies at the molecular, biochemical, cellular and intact animal levels, indicate that transversion of Ser96 to Ala results in abolishment of an HRC phosphorylation site by Fam20C kinase and dysregulation of SR Ca2+ cycling. This is mediated through aberrant SR Ca2+ release by the ryanodine receptor (RyR2) quaternary complex, due to the impaired HRC/triadin interaction, and depressed SR Ca2+ uptake by the sarco/endoplasmic reticulum Ca2+ ATPase (SERCA2) pump, due to the impaired HRC/SERCA2 interaction. Pharmacological intervention with KN-93, an inhibitor of Ca2+/calmodulin-dependent protein kinase II (CaMKII), in the HRC Ser96Ala mouse model, reduced the occurrence of malignant cardiac arrhythmias. Herein, we summarize the current evidence on the pivotal role of HRC in the regulation of cardiac rhythmicity and the importance of HRC Ser96Ala as a genetic modifier for arrhythmias in the setting of heart failure.

Keywords: Calcium, Homeostasis, contractility, Ion Channels, arrhythmia

Received: 21 Jul 2018; Accepted: 11 Sep 2018.

Edited by:

Gaetano Santulli, Columbia University, United States

Reviewed by:

Yoram Etzion, Ben-Gurion University of the Negev, Israel
Crystal M. Ripplinger, University of California, Davis, United States
Pietro Mesirca, Centre national de la recherche scientifique (CNRS), France  

Copyright: © 2018 Arvanitis, Vafiadaki, Johnson, Kranias and Sanoudou. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Despina Sanoudou, National and Kapodistrian University of Athens, 4th Department of Internal Medicine, Attikon Hospital, Athens, 10679, Greece,