Catecholamine-dependent cAMP signalling is a key regulator of excitation-contraction coupling and the incorrect activation of this pathway is a hallmark of disease states such as cardiac hypertrophy and heart failure (HF). In addition to β-adrenergic receptors (β-AR), several other types of Gs-coupled receptors signal in the heart through the generation of cAMP. Cardiac signalling of different cAMP-elevating hormones has long been known to result in distinct functional outputs. This observation has led to the recognition that mechanisms must be in place that allow for specificity of response and that alterations of such mechanisms may result in cardiac disease, although the nature of such mechanisms and the disease-associated changes are poorly defined. The question of how cAMP signalling fidelity is achieved is therefore of fundamental importance for understanding cardiac function in health and disease. Spatial control of cAMP signal propagation has emerged as a key mechanism responsible for specificity of response. That is, activation of individual GPCRs generates spatially restricted pools of cAMP within distinct subcellular compartments, leading to the activation of selected subsets of the cAMP effector, protein kinase A (PKA). PKA subsets are clustered on a scaffold of A-kinase anchoring proteins (AKAPs) into microdomains together with other key downstream elements of the signalling cascade and in the vicinity of specific effectors such as receptors, phospholamban, and ion channels. Based on this model, contractility is affected by changes in cAMP levels in a defined subcellular compartment whereas cAMP changes in other compartments may affect gene transcription or apoptosis, for example. Although HF is characterized by down regulation of cAMP signals, elevation of cAMP via activation of the adrenergic system in HF patients correlates directly with shortened survival. This apparent paradox may be explained by failure to achieve the necessary spatial accuracy when manipulating bulk cAMP levels through β-AR activation, resulting in deleterious, off-target effects. Therefore a detailed understanding of the molecular mechanisms that regulate compartmentalised cAMP signalling may help developing novel strategies for the treatment of heart disease. We are using a combination of real-time imaging, biochemical and genetic approaches to study the spatio-temporal dynamics of cAMP in intact living cells. We aim at understanding the architectural and regulatory principles by which intracellular cAMP signalling networks achieve the plasticity and context-sensitivity necessary for a cardiac myocyte to function and we are dissecting how alterations of these networks may be responsible for the development of cardiac disease.