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Multiple forms of cAMP phosphodiesterases (PDE), adenylate cyclase and protein kinase A (PKA) allow cells to tailor the responsiveness of the cAMP-signalling system and to allow for its dynamic adjustment. Multiple forms of these enzymes confer spatial and temporal characteristics on cAMP signalling so as to affect compartmentalised responses within a single cell type. The ability to breach the PKA activation threshold can depend upon either or both the activation of adenylate cyclase and inhibition of specific PDE isoforms.