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Authors: Dagmar Harzheim, Amarnath Talasila, Mehregan Movassagh, Roger S-Y. Foo, Nichola Figg, Martin D. Bootman and H. Llewelyn Roderick

Dagmar Harzheim

The Babraham Institute, Cambridge, UK

Amarnath Talasila

The Babraham Institute, Cambridge, UK

Mehregan Movassagh

Addenbrooke's Centre for Clinical Investigation, Cambridge, UK

Roger S-Y. Foo

Addenbrooke's Centre for Clinical Investigation, Cambridge, UK

Nichola Figg

Addenbrooke's Centre for Clinical Investigation, Cambridge, UK

Martin D. Bootman

The Babraham Institute, Cambridge, UK

H. Llewelyn Roderick

Corresponding author: Llewelyn.roderick@bbrsc.ac.uk
The Babraham Insitute and University of Cambridge, Cambridge, UK

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Abstract:

Cardiac hypertrophy is associated with profound remodelling of Ca²⁺ signalling pathways. During the early, compensated stages of hypertrophy, Ca²⁺ fluxes may be enhanced to facilitate greater contraction, whereas as the hypertrophic heart decompensates, Ca²⁺ homeostatic mechanisms are dysregulated leading to decreased contractility, arrhythmia and death. Although ryanodine receptor Ca²⁺ release channels (RyR) on the sarcoplasmic reticulum (SR) intracellular Ca²⁺ store are primarily responsible for the Ca²⁺ flux that induces myocyte contraction, a role for Ca²⁺ release via the inositol 1,4,5-trisphosphate receptor (InsP₃R) in cardiac physiology has also emerged. Specifically, InsP₃-induced Ca²⁺ signals generated following myocyte stimulation with an InsP₃-generating agonist (e.g. endothelin, ET-1), lead to modulation of Ca²⁺ signals associated with excitation-contraction coupling (ECC) and the induction of spontaneous Ca²⁺ release events that cause cellular arrhythmia. Using myocytes from spontaneously hypertensive rats (SHR), we recently reported that expression of the type 2 InsP₃R (InsP₃R2) is significantly increased during hypertrophy. Notably, this increased expression was restricted to the junctional SR in close proximity to RyRs. There, enhanced Ca²⁺ release via InsP₃Rs serves to sensitise neighbouring RyRs causing an augmentation of Ca²⁺ fluxes during ECC as well as an increase in non-triggered Ca²⁺ release events. Although the sensitization of RyRs may be a beneficial consequence of elevated InsP₃R expression during hypertrophy, the spontaneous Ca²⁺ release events are potentially of pathological significance giving rise to cardiac arrhythmia. InsP₃R2 expression was also increased in hypertrophic hearts from patients with ischemic dilated cardiomyopathy and aortically-banded mice demonstrating that increased InsP₃R expression may be a general phenomenon that underlies Ca²⁺ changes during hypertrophy.

Article Addendum to:
D Harzheim, M Movassagh, RS Foo, O Ritter, A Tashfeen, SJ Conway, MD Bootman, HL Roderick. Increased InsP3Rs in the junctional sarcoplasmic reticulum augment Ca2+ transients and arrhythmias associated with cardiac hypertrophy. Proc Natl Acad Sci U S A 2009; 106: 11406-11
PMID: 19549843 DOI: 10.1073/pnas.0905485