he ATP binding site. Nine membrane-bound and one soluble adenylyl cyclase have been so far identified. Most tissues express more than one AC and almost every AC is expressed in the brain. cAMP binding to the PKA complex leads to dissociation of the catalytic subunits from the holoenzyme. In the inactive state, the holoenzyme consists of two catalytic subunits (C) bound noncovalently to a regulatory dimer (RI or RII). There are two type I and two type II regulatory subunits and three catalytic subunits in humans; rodents express only two catalytic subunits. Each regulatory subunit has two cAMP binding sites; type I has a higher affinity for cAMP than type II. Binding of four molecules of cAMP to the regulatory dimer induces a conformational change that leads to dissociation of the holoenzyme and release of the catalytic monomers. cAMP is hydrolyzed by phosphodiesterases (PDE), the only enzymes degrading cycling nucleotides. The 21 mammalian genes are subdivided in 11 families based on kinetic and pharmacological properties. Of these, 3 families are specific for cAMP, 3 other for cGMP and 5 hydrolyze both. PDEs not only contribute to the regulation of cAMP concentration but also modulate the duration and extent of cAMP signaling, and thus of PKA. The compartmentalization of PKA is mediated by the AKAP family of scaffold proteins (A Kinase Anchoring Protein). AKAPs bring together PKA (and other kinases) along with phosphatases and phosphodiesterases, in some cases AC and target proteins to fine tune the many outcomes of PKA signaling. 14 Akap genes in mammals give rise to more than 50 proteins. Primarily they target the regulatory type II subunits; a few possess dual specificity and bind both subunits types. The various combinations of AKAP-PKA allow for the diversity of cellular and tissue distribution of the serine/threonine PKA complexes and the modulation of their function and underlie the extensive use of this intracellular pathway. PKA cross-talks or integrates with other signaling pathways. The PKA signaling pathway has been implicated in many cellular and physiological processes, from metabolism and reproduction, to cardiac function, memory and learning. To see the ontology report for annotations, GViewer and download click here [click to see the ontology report for related GO term GO:0010737 and entry at Reactome - REACT_15530.1]...(less)