Description
Adenosine 3'5'-cyclic monophosphate (cAMP) is a ubiquitous second messenger that mediates a diverse range of cellular processes in all organisms from bacteria to higher eukaryotes. It is converted from adenosine triphosphate (ATP) by adenylyl cyclases (ACs), and is inactivated by phosphodiesterases (PDEs) which catalyze its hydrolysis to 5'-AMP. In mammals, upon interaction with extracellular ligands, G protein coupled receptors (GPCRs) linked to Gαs activate the family of nine transmembrane ACs to increase intracellular cAMP. In contrast, GPCRs associated with Gαi/o inhibit the synthesis of cAMP by transmembrane ACs. With the exception of AC9, transmembrane ACs can be activated by forskolin, a plant diterpene commonly used to raise cAMP levels in cells. A divalent cation-dependent soluble AC (sAC) isoform also exists. It is activated by bicarbonate ions and can be found in the cytosol and in subcellular organelles.
The physiological roles of cAMP are mediated via multiple effector molecules. Binding of cAMP to protein kinase A (PKA) holoenzyme induces conformational changes and releases the catalytic subunit to phosphorylate target substrates on serine/threonine residues. cAMP binding to the guanine nucleotide exchange factors Epac1/2 (exchange protein activated by cAMP, also known as cAMP-GEF-I and cAMP-GEF-II) mediates the exchange of GDP for GTP on the small molecular weight G proteins Rap-1 and -2. Activated Rap proteins are important in multiple cellular processes including adhesion and exocytosis. cAMP can also activate cyclic nucleotide-gated ion channels (CNG) by binding directly to the nonselective cation channel proteins that are expressed in various tissues. cAMP signaling is spatially and temporally regulated, allowing for the selective activation of a subset of targets. A-kinase anchoring proteins (AKAPs) provide the platform for the assembly of signalsomes consisting of cAMP effectors (PKA and/or Epac) and their substrates, together with signal terminators including phosphatases and PDEs.
In response to increases in intracellular cAMP, a wide variety of cell types possess mechanisms for exporting cAMP to the extracellular space. In mammals, plasma and urine cAMP concentrations can become highly elevated under certain physiological conditions. Extracellular cAMP is known to exert physiological actions on diverse cell types, in part through the cAMP-adenosine pathway where cAMP is converted to adenosine via ecto-PDEs and ectonucleotidases