Ins(1,4,5)P3 receptors and inositol phosphates in the heart-evolutionary artefacts or active signal transducers?

Abstract

The generation of the second messenger inositol 1,4,5-trisphosphate (Ins(1,4,5)P(3)) and its associated release of Ca(2+) 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 Ca(2+) release. However, despite the presence of the requisite Ins(1,4,5)P(3) signaling machinery, excitable cells such as cardiac myocytes employ a robust alternate system of intracellular Ca(2+) release, namely, a coupled system of Ca(2+) influx, followed by Ca(2+) release via the IP(3)R-related ryanodine receptors. In these systems, Ins(1,4,5)P(3) 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)P(3) generation and Ins(1,4,5)P(3) receptor (IP(3)Rs) 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)P(3) generation in both arrhythmogenic and hypertrophic responses, and possible mechanisms involving Ins(1,4,5)P(3) are discussed. While Ins(1,4,5)P(3) is unlikely to be a key player in cardiac excitation-contraction (EC) coupling, its potential role in an alternate Ca(2+) release system to signal changes in gene transcription warrants further investigation. Such studies will help to determine whether cardiac Ins(1,4,5)P(3) generation represents a vestigial pathway or plays an active role in cardiac signaling.