In the cytosol, cAMP is not evenly distributed but rather forms submembranous spatially discrete pools generated in microdomains containing AC, PDE next to PKA localized by A-kinase-anchoring proteins (AKAPs) ( 20). In addition to PKA, CREB, CREM, and ATF-1 can all be phosphorylated by many other kinases, and the action of PKA is counterbalanced by specific protein phosphatases.īasal cytosolic cAMP levels are in the low micrometer range ( 19). In addition to PKA activation, cAMP also directly modulates the activity of guanine-nucleotide-exchange factor (GEF) exchange proteins (Epacs) and cyclic nucleotide-gated channels (CNGs) ( 16) all with important roles in cellular functions ( 17, 18). Phosphorylated CREB, CREM, and ATF-1 interact with the transcriptional coactivators CREB-binding protein (CBP) and p300 when bound to cAMP-response elements (CREs) in target genes ( 15). In addition, cAMP-activated PKA binds and phosphorylates cAMP-responsive transcription factors, including cAMP-response element binding protein (CREB), members of the cAMP-responsive element modulator/inducible cAMP early repressor (CREM/ICER) protein family ( 14), activating transcription factor-1 (ATF-1), NFκB, and nuclear receptors (see Figure 1). Upon binding of cAMP to the regulatory subunits, PKA dissociates into its regulatory and catalytic subunits and the catalytic subunits phosphorylate specific Ser and Thr residues on numerous target proteins initiating successive signaling cascades, particularly in nutrient metabolism ( 13). Most prominent, it activates the cAMP-dependent protein kinase A I (PKA) ( 12) (see Figure 1). Additional families hydrolyze both cAMP and cGMP (PDE 1, 2, 3, 10, and 11), establishing cross-regulation of both pathways with important implications in the utility of pharmacotherapeutic agents targeting cyclic nucleotide metabolism ( 10, 11).Īs a second messenger, cyclic AMP serves in multiple downstream pathways. Contributing to the complexity of the pathway, some PDE families are strictly cAMP-specific (PDE 4, 7, and 8), whereas others are cyclic guanosine monophosphate (cGMP)-specific (PDE 5, 6, and 9) ( 8, 9).

Certain PDE increase their activities in response to cAMP and cAMP stimulates the synthesis of new PDE mRNA ( 6, 7), resulting in a feedback loop between cAMP levels and PDE activity. PDE comprise more than 100 enzyme variants divided into 11 families ( 5) based on their structure, specificity for, and modulation by, cyclic nucleotides. In addition to AC expression and activity cAMP homeostasis is regulated by a superfamily of phosphodiesterases (PDE) that degrade intracellular cyclic nucleotides. AC vary in distribution and developmental expression and their regulation is complex and isozyme specific. In vertebrates, AC comprise nine membrane-bound isoforms and one soluble isoform ( 4). A family of enzymes called adenylate cyclases (AC) catalyzes cAMP formation from ATP. The cAMP PathwayĬyclic adenosine monophosphate, identified in 1957 ( 2) as the first intracellular second messenger of extracellular ligand action, is now established as a universal regulator of metabolism and gene expression in all life forms ( 3). This review aims to shed light on the variety of processes influenced by cAMP in the immune system with regard to treatment options in diseases. Within the immune system, cAMP regulates pro- and anti-inflammatory activities: drugs that elevate intracellular cAMP levels reduce the production of pro-inflammatory mediators and increase the production of anti-inflammatory factors in numerous immune cells. Cyclic adenosine monophosphate (cAMP) was the first discovered intracellular second messenger of extracellular ligand action ( 2). Thereby second messengers serve to greatly amplify the strength of the original first signal.

Second messengers serve as initiating components of intracellular signal transduction cascades that transmit signals by cellular messengers that depend on extracellular signaling molecules ( 1). Cells must be able to sense and integrate countless extracellular and intracellular signals and adapt their cellular functions.

Non cyclic amp molecule