Modelling the inositol 1,4,5-trisphosphate/calcineurin signal transduction pathway in the cardiac myocyte

Abstract

The intracellular mechanisms regulating pathological concentric cardiac hypertrophy, strongly implicated in the development congestive heart disease, are currently not understood at the quantitative level. The IP3 / calcineurin signal transduction pathway is highly significant to the development of the disease, stimulating the hypertrophic transcription factor NFAT. To increase understanding of this pathway in the cardiac myocyte, several novel models of a number of molecular processes, from extracellular agonist to the nuclear entry of DNA-ready transcription factor, are constructed. These include models for the production and degradation of the intracellular second messenger IP3 on stimulation with extracellular hypertrophic agonists, the dual regulation of the enzyme calcineurin by calmodulin and calcium, and the cytosolic-nuclear-cytosolic cycling of NFAT after calcium stimulation. A cardiac-dominant isoform-specific model of the IP3 receptor (IP3R2) is also presented. Data for these models is both drawn from the current molecular biology literature and estimated by model fitting to published experimental observations in cell systems. All models were developed using the CellML model exchange protocol, and leading practices relating to the definition of flexible, reusable model modules implemented in that technology were also developed. Analysis of the models Ied to a number of insights about the biological processes they represent. For the first time the key drivers of the IP3 production and degradation processes have been determined. The importance of receptor kinetics was discovered and confirmed by successfully simulating responses from two different hormones. Mechanistic details of the dual regulation of calcineurin were predicted via two different modelling approaches. The NFAT model replicates calcium oscillation sensitivity as observed experimentally and also indicates a high sensitivity to a signal transduction-induced calcium transient against a background of excitation-contraction driven calcium oscillations. These insights further the understanding of some of the mechanisms of cardiac hypertrophy and have Ied to predictions that should drive future experimental measurement of the processes of this system.