Abstract 078: Differential Phosphorylation of Inositol 1,4,5-triphophate Receptor by CaMKIId During Cardiac Remodeling
Natesan Sankar1, Sukriti Dewan1, Joshua Maxwell1, Donald Bers2, Joan Heller Brown3, Jeffery Molkentin4, Pieter deTombe1, Gregory Mignery1. 1Department of Cell and Molecular Physiology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL. 2Department of Physiology, Department of Pharmacology University of California at Davis, Davis, CA. 3Department of Pharmacology, University of California, San Diego, La Jolla, CA. 4Howard Hughes Medical Institute, Molecular Cardiovascular Biology, Cincinnati Children’s Hospital, Cincinnati, OH. In cardiac myocytes the type-2 isoform of the inositol 1,4,5-triphosphate receptor (InsP3R2) Ca2+ release channel is expressed predominantly in the nuclear envelope. InsP3R2 releases intracellular Ca2+ bidirectionally towards the cytoplasm and nucleoplasm in response to an array of pro-hypertrophic signaling. Thus, InsP3R2 mediated Ca2+ release may contribute to both Excitation-Contraction Coupling (ECC) and Excitation-Transcription Coupling (ETC) during normal and pathophysiologic conditions such as cardiac remodeling. However, the regulation of InsP3R2 mediated Ca2+ release and its role in ECC and ETC during cardiac remodeling is not fully understood. We have shown that CaMKIIδ and InsP3R2 forms a signaling complex in the heart and CaMKII mediated phosphorylation of InsP3R2 at S150 modulates its intrinsic Ca2+ channel activity. Here we show that InsP3R2 is differentially phosphorylated by CaMKIIδB and CaMKIIδC, the predominant nucleoplasmic and cytoplasmic isoforms respectively, in cardiac myocytes. Using adult rat cardiac myocytes we show that the differential phosphorylation by CaMKII of InsP3R2 at S150 leads to elevated nuclear Ca2+ signaling and diminished release towards the cytoplasm. Additionally we show that the InsP3R2 was phosphorylated in the hearts of Angiotensin II infused and pressure overload induced cardiac remodeling animal models. Finally, we show that there was an increase in InsP3R2 phosphorylation in human heart-failure samples compared to non-failing hearts. Collectively our studies demonstrate that, CaMKIIδ mediated regulation of InsP3R2 Ca2+ channel activity contributes to ECC and ETC during all the phases of cardiac remodeling processes.
- © 2013 by American Heart Association, Inc.