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 Ca²⁺ entry across the sarcolemma during the action potential, it is the release of Ca²⁺ from the sarcoplasmic reticulum (SR) intracellular Ca²⁺ store via ryanodine receptors (RyRs) that plays the major role in induction of contraction. Ca²⁺ also acts as a key intracellular messenger regulating transcription underlying hypertrophic growth. Although Ca²⁺ release via RyRs is by far the greatest contributor to the generation of Ca²⁺ transients in the cardiomyocyte, Ca²⁺ is also released from the SR via inositol 1,4,5-trisphosphate (InsP₃) receptors (InsP₃Rs). This InsP₃-induced Ca²⁺ release modifies Ca²⁺ transients during ECC, participates in directing Ca²⁺ to the mitochondria, and stimulates the transcription of genes underlying hypertrophic growth. Central to these specific actions of InsP₃Rs is their localization to responsible signalling microdomains, the dyad, the SR-mitochondrial interface and the nucleus. In this review, the various roles of InsP₃R in cardiac (patho)physiology and the mechanisms by which InsP₃ 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'.