Novel cAMP signalling paradigms: therapeutic implications for airway disease

Abstract

Since its discovery over 50 years ago, cAMP has been the archetypal second messenger introducing students to the concept of cell signalling at the simplest level. As explored in this review, however, there are many more facets to cAMP signalling than the path from Gs-coupled receptor to adenylyl cyclase (AC) to cAMP to PKA to biological effect. After a brief description of this canonical cAMP signalling pathway, a snapshot is provided of the novel paradigms of cAMP signalling. As in the airway the cAMP pathway relays the major bronchorelaxant signal and as such is the target for frontline therapy for asthma and COPD, particular emphasis is given to airway disease and therapy. Areas discussed include biased agonism, continued signalling following internalization, modulation of cAMP by AC, control of cAMP degradation, cAMP and calcium crosstalk, Epac-mediated signalling and finally the implications of altered genotypes will be considered. LINKED ARTICLESThis article is part of a themed section on Novel cAMP Signalling Paradigms. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.166.issue-2 Abbreviations AC, adenylyl cyclase; ASM, airway smooth muscle; CFP, cyan fluorescent protein; COPD, chronic obstructive pulmonary disease; CREB, cAMP response element binding; Epac, exchange protein directly activated by cAMP; GEF, guanine nucleotide exchange factor; GRK, G-protein coupled receptor kinase; hASM, human airway smooth muscle; IP3, inositol trisphosphate; RACK1, receptors for activated C kinase 1; SERCA, sarco/endoplasmic reticulum Ca 2+ -ATPase; SOCC, store-operated calcium channel; TSH, thyroid-stimulating hormone; YFP, yellow fluorescent protein cAMP is the classical second messenger discovered by Earl W Sutherland Jr. and Theodore W Rall in 1956 (Sutherland andRall, 1958). To date, research into cAMP has led to five Nobel awards (Beavo and Brunton, 2002) and is the subject of almost 100 000 publications on PubMed. In the last decade, in particular, the generation and enhanced use of fluorescent probes allowing quantification/visualisation of cAMP signalling at a pharmacological, spatial and temporal level has added significantly to our understanding of this pathway (Lohse et al., 2008;Hill et al., 2010).In the airways, cAMP is a critical regulator of airway tone being the major pro-relaxant effector in airway smooth muscle (ASM) bundles. As such, it is a key therapeutic target in airway disease being the transducer of the signal induced by clinically used b2-adrenoceptor agonists (e.g. indacaterol, formoterol, salmeterol) which results in bronchodilation and symptomatic relief. Although outside the scope of this review, it should be mentioned that in addition to its pro-relaxant role in ASM, cAMP modulates a range of diverse cellular events pertinent to airway function including the production and secretion of inflammatory mediators and extracellular matrix, proliferation, migration and in epithelial cells mucus secretion, wound healing, anion transport and ciliary beating (Sal...

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