Emerging roles of inositol 1,4,5-trisphosphate signaling in cardiac myocytes

Inositol 1,4,5-trisphosphate (IP3) is a ubiquitous intracellular messenger regulating diverse functions in almost all mammalian cell types. It is generated by membrane receptors that couple to phospholipase C (PLC), an enzyme which liberates IP3 from phosphatidylinositol 4,5-bisphosphate (PIP2). The major action of IP3, which is hydrophilic and thus translocates from the membrane into the cytoplasm, is to induce Ca2+ release from endogenous stores through IP3 receptors (IP3Rs). Cardiac excitation–contraction coupling relies largely on ryanodine receptor (RyR)-induced Ca2+ release from the sarcoplasmic reticulum. Myocytes express a significantly larger number of RyRs compared to IP3Rs (~100:1), and furthermore they experience substantial fluxes of Ca2+ with each heartbeat. Therefore, the role of IP3 and IP3-mediated Ca2+ signaling in cardiac myocytes has long been enigmatic. Recent evidence, however, indicates that despite their paucity cardiac IP3Rs may play crucial roles in regulating diverse cardiac functions. Strategic localization of IP3Rs in cytoplasmic compartments and the nucleus enables them to participate in subsarcolemmal, bulk cytoplasmic and nuclear Ca2+ signaling in embryonic stem cell-derived and neonatal cardiomyocytes, and in adult cardiac myocytes from the atria and ventricles. Intriguingly, expression of both IP3Rs and membrane receptors that couple to PLC/IP3 signaling is altered in cardiac disease such as atrial fibrillation or heart failure, suggesting the involvement of IP3 signaling in the pathology of these diseases. Thus, IP3 exerts important physiological and pathological functions in the heart, ranging from the regulation of pacemaking, excitation–contraction and excitation–transcription coupling to the initiation and/or progression of arrhythmias, hypertrophy and heart failure.