Abstract

The generation of the second messenger inositol 1,4,5-trisphosphate (Ins(1,4,5)P₃) and its associated release of Ca²⁺ from internal stores is a highly conserved module in intracellular signaling from Drosophila to mammals. Many cell types, often nonexcitable cells, depend on this pathway to couple external signals to intracellular Ca²⁺ release. However, despite the presence of the requisite Ins(1,4,5)P₃ signaling machinery, excitable cells such as cardiac myocytes employ a robust alternate system of intracellular Ca²⁺ release, namely, a coupled system of Ca²⁺ influx, followed by Ca²⁺ release via the IP₃R-related ryanodine receptors. In these systems, Ins(1,4,5)P₃ signaling pathways appear to be largely dormant. In this review, we consider the general features of inositol phosphate (InsP) responses in cardiac myocytes and the molecules mediating these responses. The spatial localization of Ins(1,4,5)P₃ generation and Ins(1,4,5)P₃ receptor (IP₃Rs) is likely of key importance, and we examine the state of knowledge in atrial, ventricular, and Purkinje myocytes. Several studies have implicated Ins(1,4,5)P₃ generation in both arrhythmogenic and hypertrophic responses, and possible mechanisms involving Ins(1,4,5)P₃ are discussed. While Ins(1,4,5)P₃ is unlikely to be a key player in cardiac excitation–contraction (EC) coupling, its potential role in an alternate Ca²⁺ release system to signal changes in gene transcription warrants further investigation. Such studies will help to determine whether cardiac Ins(1,4,5)P₃ generation represents a vestigial pathway or plays an active role in cardiac signaling.

Keywords: Inositol phosphates; Phospholipase C; Arrhythmia; Hypertrophy

Abbreviations: α₁-AR, α₁-adrenergic receptor; ANP, atrial natriuretic factor; APD, action potential duration; CaMKII, Ca²⁺/calmodulin-dependent protein kinase II; CnA, calcineurin A; DAG, sn-1,2-diacylglycerol; EC, excitation–contraction; EGF, epidermal growth factor; ER, endoplasmic reticulum; ERK, extracellular signal-regulated kinase; GEF, guanyl nucleotide exchange factor; GPCR, G protein-coupled receptor; GSK, glycogen synthase kinase; HDAC, histone deacetylase; INPP, inositol polyphosphate 1-phosphatase; InsP, inositol phosphate; Ins(1,4,5)P₃, inositol(1,4,5)trisphosphate; Ins(1,4)P₂, inositol(1,4)bisphosphate; IP₃R, Ins(1,4,5)P₃ receptor; JNK, c-Jun-NH₂-terminal kinase; MAPK, mitogen-activated protein kinase; MEF2, myocyte enhancer factor 2; MLC, myosin light chain; NFAT, nuclear factor of activated T-cells; PLC, phospholipase C; PtdInsP, phosphatidylinositol(4)monophosphate; PtdInsP₂, phosphatidylinositol(4,5)bisphosphate; SERCA, sarco/endoplasmic reticulum Ca²⁺-ATPase; SRF, serum response factor

Article Outline

1. Introduction

2. Cardiac excitation–contraction coupling

3. Inositol(1,4,5)trisphosphate-mediated Ca²⁺ responses—a general model

4. Inositol phosphate responses in cardiomyocytes

5. Inositol(1,4,5)trisphosphate receptor location in cardiomyocytes

6. Inositol(1,4,5)trisphosphate and arrhythmogenesis

7. Inositol(1,4,5)trisphosphate and cardiac hypertrophy

8. Inositol(1,4,5)trisphosphate receptor and cardiac development

9. Conclusions and future study directions

References