Response to Letter Regarding Article “Inositol 1,4,5-Trisphosphate Receptors and Human Left Ventricular Myocytes”
Authors: Sergio Signore, Andrea Sorrentino, João Ferreira-Martins, Ramaswamy Kannappan, Mehrdad Shafaie, Fabio Del Ben, Kazuya Isobe, Christian Arranto, Ewa Wybieralska, Andrew Webster, Fumihiro Sanada, Barbara Ogórek, Hanqiao Zheng, Xiaoxia Liu, Federica del Monte, David A. D’Alessandro, Oriyanhan Wunimenghe, Robert E. Michler, Toru Hosoda, Polina Goichberg, Annarosa Leri, Jan Kajstura, Piero Anversa, Marcello Rota
Journal: Circulation (2014)

We thank Drs Heidrich and colleagues for their comments on our study discussing the role of inositol 1,4,5-trisphosphate receptors (IP3Rs) in ventricular myocytes. 1We documented that IP3Rs are present and operative in the rodent and human ventricular myocardium and that stimulation of G αq -protein-coupled receptors promotes IP3R-mediated Ca 2+ release.This adaptation provides inotropic support but favors electric instability.As pointed out by Dr Heidrich and colleagues, our report did not address the contribution of endogenous IP3R-regulatory proteins 2 to the electrophysiological and contractile properties of ventricular myocytes.Specifically, they raised the possibility that chromogranin B, a sarcoplasmic reticulum Ca 2+ -binding protein, interacts with IP3Rs 3 and modulates myocyte behavior after G αq -protein-coupled receptor stimulation.The relationship between chromogranin B and IP3Rs may be particularly relevant to the failing heart, a condition characterized by upregulation of both chromogranin B and IP3Rs.We share this view, and additional experiments are warranted to elucidate several important aspects of IP3R activation.Consistent with the role of chromogranin B in the control of intracellular Ca 2+ , other regulatory mechanisms may alter IP3Rs and Ca 2+ translocation in myocytes physiologically and in pathological conditions.Unpublished observations from our laboratory indicate that β-adrenergic stimulation induces IP3R-mediated Ca 2+ release in cardiac progenitor cells (CPCs).In this cell class, intracellular oscillatory events originate as a consequence of the translocation of Ca 2+ from the endoplasmic reticulum to the cytoplasm via IP3Rs. 4n contrast, crucial variables of myocyte Ca 2+ homeostasis, voltagedependent transmembrane Ca 2+ fluxes, and ryanodine receptor Ca 2+ release are not involved in this process. 4Exposure of human CPCs to the β-adrenergic agonist isoproterenol increases by ≈2-fold the fraction of cells displaying intracellular Ca 2+ oscillations.These findings support the notion that IP3R channels undergo posttranslational modifications mediated by protein kinase A, a target of β-adrenergic receptor signaling. 5Myocytes are the progeny of CPCs, and similar mechanisms may be operative in both cell categories, suggesting that IP3Rs participate at distinct levels in the response of the myocardium to β-adrenergic ligands.The multiple endogenous and exogenous regulators of IP3Rs have yet to be identified, and only the integration of molecular protocols with physiological assays will provide a thorough understanding of the function of IP3Rs in the modulation of the properties of cardiomyocytes and CPCs.Whether IP3Rs are implicated not only in the initiation of CPC growth but also in lineage specification and myocyte differentiation is a critical unanswered question.However, the recognition that IP3Rs are expressed in CPCs and cardiomyocytes suggests that they may be implicated in the control of myocyte renewal during the normal wear and tear of the organ and in the repair process after myocardial injury.