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

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’.