Compartmentation of cAMP in Cardiomyocytes

The concept of compartmentalized signaling stems from studies of the cAMP pathway in the heart. In cardiac myocytes, intracellular cAMP levels can be augmented by catecholamine as well as by a large number of hormones and circulating factors. These different "first messengers" act through specific heptahelical receptors coupled to heterotrimeric Gs proteins, which activate cAMP synthesis by adenylyl cyclases (AC). In some cases, such as catecholamine or isoprenaline (ISO) binding to β1-adrenergic receptors (β1AR), cAMP elevation causes a dramatic increase in cardiac beating frequency (positive chronotropy), in cardiac force of contraction, and in cardiac relaxation speed. These effects are mainly due to the concerted phosphorylation of key proteins of the excitation–contraction coupling (ECC) by cAMP-dependent protein kinase (PKA): L-type Ca2+ channels (LTCC), phospholamban (PLB), ryanodine receptors (RyR), and troponin I (TnI). In addition to specialized membrane structures that influence the organization of the cAMP cascade, degradation of cAMP by cyclic nucleotide phosphodiesterases (PDEs) appears critical for the formation of dynamic cAMP microdomains. GPCRs positively coupled to cAMP may not act exclusively through the classical Gs/cAMP/PKA cascade. The property of PDE4 long forms' ability to be phosphorylated and activated by PKA and to bind to AKAPs allows efficient suppression of βAR cAMP by these enzymes. The fact that PDE inhibition decreased the proportion of particulate vs cytosolic cAMP suggests that these enzymes limit the amount of cAMP diffusing from the membrane to the cytosol upon βAR stimulation.