Distinct PKA and Epac compartmentalization in airway function and plasticity

Asthma and chronic obstructive pulmonary disease (COPD) are obstructive lung diseases characterized by airway obstruction, airway inflammation and airway remodelling. Next to inflammatory cells and airway epithelial cells, airway mesenchymal cells, including airway smooth muscle cells and (myo)fibroblasts, substantially contribute to disease features by the release of inflammatory mediators, smooth muscle contraction, extracellular matrix deposition and structural changes in the airways. Current pharmacological treatment of both diseases intends to target the dynamic features of the endogenous intracellular suppressor cyclic AMP (cAMP). This review will summarize our current knowledge on cAMP and will emphasize on key discoveries and paradigm shifts reflecting the complex spatio-temporal nature of compartmentalized cAMP signalling networks in health and disease. As airway fibroblasts and airway smooth muscle cells are recognized as central players in the development and progression of asthma and COPD, we will focus on the role of cAMP signalling in their function in relation to airway function and plasticity. We will recapture on the recent identification of cAMP-sensing multi-protein complexes maintained by cAMP effectors, including A-kinase anchoring proteins (AKAPs), proteins kinase A (PKA), exchange protein directly activated by cAMP (Epac), cAMP-elevating seven-transmembrane (7TM) receptors and phosphodiesterases (PDEs) and we will report on findings indicating that the pertubation of compartmentalized cAMP signalling correlates with the pathopysiology of obstructive lung diseases. Future challenges include studies on cAMP dynamics and compartmentalization in the lung and the development of novel drugs targeting these systems for therapeutic interventions in chronic obstructive inflammatory diseases.