Development of a platform for the assessment of cardioactive compounds by quantitative and simultaneous analysis of subcellular cAMP signalling and

(title cont) cardiac myocyte electro-mechanical effects |

Many elements in the heart regulate the speed and strength of heartbeats, including the messenger molecule called cyclic adenosine monophosphate (cAMP). Chemical signals, like hormones, can increase cellular cAMP that delivers the signal through phosphorylation of many targets, like ion channels, to promote or inhibit their activity. One example is when adrenaline is released during our flight-or-fight response to increase cAMP in heart cells and drive a faster heart rate. We understand that cAMP signalling operates in cardiac cells by activating targets that regulate different cellular functions depending on their subcellular localisation. Therefore, if we stimulate cAMP signalling in a specific subcellular area, the effects on the heart will be distinct to when cAMP is stimualted cell-wide. Computational modelling will be used to create an overarching model describing the signalling pathway of: 1. chemical signal, 2. spatial cAMP increase, 3. spatial target activity change, and 4. heart rate and contractility change. This will be informed through combining experiments that investigate a particular chain of events such as one experiment on signal to localised cAMP increase and another experiment on cAMP concentration to target (e.g. ion channel) activity. We can use this model to predict changes in heart rate and contractility from drugs by simulating their effects on the cAMP signalling pathway

BBSRC Priorities: Systems approaches to the biosciences; Data-driven biology; Replacement, refinement and reduction (3Rs) in research using animals