Inositol 1,4,5-trisphosphate receptors in cardiomyocyte physiology and disease

Abstract

The contraction of cardiac muscle underlying the pumping action of the heart is mediated by the process of excitation-contraction coupling (ECC). While triggered by Ca 2+ entry across the sarcolemma during the action potential, it is the release of Ca 2+ from the sarcoplasmic reticulum (SR) intracellular Ca 2+ store via ryanodine receptors (RyRs) that plays the major role in induction of contraction. Ca 2+ also acts as a key intracellular messenger regulating transcription underlying hypertrophic growth. Although Ca 2+ release via RyRs is by far the greatest contributor to the generation of Ca 2+ transients in the cardiomyocyte, Ca 2+ is also released from the SR via inositol 1,4,5-trisphosphate (InsP 3 ) receptors (InsP 3 Rs). This InsP 3 -induced Ca 2+ release modifies Ca 2+ transients during ECC, participates in directing Ca 2+ to the mitochondria, and stimulates the transcription of genes underlying hypertrophic growth. Central to these specific actions of InsP 3 Rs is their localization to responsible signalling microdomains, the dyad, the SR-mitochondrial interface and the nucleus. In this review, the various roles of InsP 3 R in cardiac (patho)physiology and the mechanisms by which InsP 3 signalling selectively influences the different cardiomyocyte cell processes in which it is involved will be presented. This article is part of the theme issue ‘The cardiomyocyte: new revelations on the interplay between architecture and function in growth, health, and disease’.

InsP3R-RyR channel crosstalk augments sarcoplasmic reticulum Ca2+ release and arrhythmogenic activity in post-MI pig cardiomyocytes

“…GPCR agonists that we and others have previously used to stimulate InsP 3 production in CM also engage multiple kinase cascades, which in turn influence the activity of NCX, L-type current, myofilaments and NHE with consequences for Ca 2+ dynamics and contractility [25,31,34,58,59]. Since we aimed in this study to specifically probe the influence of InsP 3 R activation on CM physiology, we chose to directly activate InsP 3 Rs with InsP 3 .…”

“…Ventricular CMs also express inositol 1,4,5'-trisphosphate receptor (InsP 3 Rs) Ca 2+ release channels (the type 2 isoform, InsP 3 R2) [21][22][23][24][25]; their expression and conductance are however substantially lower than RyRs [26][27][28]. While induction of inotropy and arrhythmogenic activity have been reported, effects of InsP 3 -induced Ca 2+ release (IICR) in healthy CM, are if detected, generally modest and vary between studies and species [23,25,29,30].…”

“…Ventricular CMs also express inositol 1,4,5'-trisphosphate receptor (InsP 3 Rs) Ca 2+ release channels (the type 2 isoform, InsP 3 R2) [21][22][23][24][25]; their expression and conductance are however substantially lower than RyRs [26][27][28]. While induction of inotropy and arrhythmogenic activity have been reported, effects of InsP 3 -induced Ca 2+ release (IICR) in healthy CM, are if detected, generally modest and vary between studies and species [23,25,29,30]. In ventricular CMs from hypertrophic or failing rodent hearts, the influence of IICR on CM physiology is greater [23,31,32], with increases in CaT amplitude, diastolic Ca 2+ and frequency of arrhythmogenic events following exposure to InsP 3 or neurohormones that promote InsP 3 generation such as Angiotensin II (AngII) and Endothelin (ET-1) reported [23,29,33,34].…”

“…Despite increased expression in disease, SR Ca 2+ release via InsP 3 Rs is minor relative to via RyRs during the CaT. To explain how this small change in cytosolic [Ca 2+ ] generated by IICR influences ECC, we and others have proposed a mechanism that involves signal amplification by RyRs [23,25,[35][36][37]. IICR is also reported to engage proximal NCX, thereby contributing to altered electrophysiology [31].…”

Increased Risk for Atrial Alternans in Rabbit Heart Failure: The Role of Ca2+/Calmodulin-Dependent Kinase II and Inositol-1,4,5-trisphosphate Signaling

“…Furthermore, levels of IP 3 signaling and expression of IP 3 R were shown to increase in various cardiac pathologies such as cardiac hypertrophy [11], HF [3,11] or AF [13]. While IP 3 dependent regulation of gene transcription contributing to hypertrophic remodeling of atria and ventricles was clearly demonstrated [11,13,53], the role of enhanced IP 3 signaling in pathophysiological atrial ECC and arrhythmogenesis is less clear. Our previous study has demonstrated that in our HF model IP 3 signaling in atria is increased leading to enhanced atrial contractility [3].…”