The activation of the cyclic nucleotide protein kinase A (PKA) and PKG by their respective second messengers is responsible for the modulation of many cellular functions in the heart including cardiac hypertrophy, strength of contraction, and ion flux. However, several studies have revealed that a general increase in cyclic nucleotide concentration in the cell is not sufficient for the specific regulation of target proteins. These studies found that PKA and PKG must be colocalized with their targets to ensure spatial–temporal control of substrate phosphorylation. This compartmentation of cyclic nucleotide signaling is accomplished by tethering the protein kinases with their respective substrates through the association with scaffolding proteins. For cAMP signaling, A-kinase anchoring proteins (AKAPs) provide a molecular mechanism for cAMP compartmentation, allowing for the precise control of PKA-mediated phosphorylation events. (cAMP, PKA, AKAP, PKG).