Cyclic adenosine monophosphate, commonly known as cyclic AMP or cAMP, is an important intracellular second messenger molecule regulated in many physiological processes. cAMP is a small, hydrophilic molecule first discovered by Dr. Earl W. Sutherland in 1958. cAMP is synthesized by adenylyl cyclase (AC), and it is broken down by phosphodiesterases (PDE). cAMP can cause a cascade of events to influence cellular function through its interaction with protein effectors such as protein kinase A (PKA), exchange proteins activated by cAMP (EPACs), cyclic nucleotide-gated ion (CNG) channels, hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. Metabolism, gene regulation, regulation of neurotransmitter synthesis, growth factors, and immune function are examples of the many biological processes that utilize cAMP regularly. Clinically, the ubiquitous nature of the cAMP pathway gives rise to therapeutic possibilities within the signal transduction system to fight against diseases such as "cancer, diabetes, heart failure, inflammation, neurological disorders, myocardial atrophy, asynodia, and mood disorders."
cAMP is generated by a complex, second messenger signal transduction system. An extracellular first messenger ligand, such as a hormone or neurotransmitter, is unable to enter a cell directly. Therefore, to exert influence, it must first interact with the receptor of a heptahelical transmembrane protein called a G protein-coupled receptor (GPCR).  Examples of first messengers include epinephrine, norepinephrine, histamine, and serotonin.
The GPCR has a Gs alpha protein attached to the system. During activation, the beta subunit is released from the Gs alpha protein. During this time, the attached inactive GDP energy is replaced with GTP. This activated GTP bound G-protein then stimulates the neighboring adenylyl cyclase (either soluble adenylyl cyclase sAC or transmembrane adenylyl cyclase tmAC) to generate the second messenger, cAMP, from ATP cyclization.
Once cAMP is generated, it then signals activation of PKA, EPAC, or other cAMP-activated proteins to stimulate physiological responses.
The production of cAMP is regulated by AC and PDE. cAMP’s main purpose is to activate PKA. An activated PKA has the ability to phosphorylate serine and threonine residues on substrate proteins which then initiate a variety of responses within the cell. For example, cAMP response element binding protein (CREB) is phosphorylated leading to regulation of gene transcription in a cell. On the other hand, PDEs degrade cAMP to 5’ AMP thus inhibiting the phosphorylating activity of PKA.
In addition to PKA, cAMP influences cellular function via a newly discovered receptor group called exchange protein directly activated by cAMP (EPAC) which cAMP-activated as two isoforms in mammals. Thus far, ex vivo cell culture model studies have demonstrated cAMP and EPAC work on cell "adhesion function, cell-cell junction, exocytosis/secretion, cell differentiation and proliferation, gene expression, apoptosis, cardiac hypertrophy." Since cAMP interacts with both PKA and EPAC families within a cell, it is noted that the interactions may act synergistically or antagonistically, depending on the function. For example, in cell proliferation and differentiation, the PKA and EPAC produce counter effects, whereas an example of synergistic effect would be in the regulation of the sodium-proton exchanger isoform.
cAMP plays a vital role in the body. The 60 years since its discovery have led to understanding many of its unique contributions and finding potential interventions for therapeutic possibilities within the pathway.
Because cAMP is prevalent in many biological processes in the body, the levels of cAMP can determine the state of function in disease or healthy state. Research shows high levels of cAMP may lead to suppression of the immune function due to disruption of white blood cell functions including "inflammation, phagocytosis, and killing of intracellular pathogens."
Microbial pathogens, such as Bordetella pertussis, take advantage of the cAMP mechanism and increase cAMP levels either directly or indirectly. As a result, this weakens cellular defense and increases the susceptibility for infection.
On the other hand, diseases including "chronic obstructive pulmonary disease (COPD), inflammation, asthma, autoimmune diseases, depression, learning and memory disorders" may be treated by increased levels of cAMP.
Understanding the signal transduction pathway of cAMP and the effect of cAMP in the body may provide routes for therapeutic intervention.
Studies support the use of the drug, forskolin, which increases the production of cAMP by acting on AC. Elevating cAMP levels with Forskolin has many benefits including increasing lipopolysaccharide (LPS)-induced inflammatory factor and vascular endothelial growth factor expression. It has a potential effect on Alzheimer disease treatment in relation to the response on AC activity in cells. Another direct way to increase cAMP effect is with Dibutyryl-cAMP, also known as Bt2cAMP, which is a cAMP analog that can cross cell membranes.
Pharmacologic agents such as rolipram, 3-isobutyl-1-methylxanthine, pentoxifylline, pyrazolopyridines, and cilostazol are examples of PDE inhibitors that raise cAMP levels. Since there are over 100 types of PDE enzymes, these drugs act upon different PDEs as inhibitors.
Caffeine is a common stimulant found in coffee, tea, sodas, chocolate, and several medications. It is consumed worldwide. Caffeine a nonselective PDE inhibitor that elevates cAMP levels. In vitro studies have shown that caffeine’s PDE inhibiting properties may influence smooth muscle relaxation. The increased concentration of cAMP causes increased phosphorylation of myosin light chain kinase (MLCK) to act on myosin light chain (MLC) in the actin-myosin contractile apparatus. This activity desensitizes MLC to calcium and calcium concentration increases. The decreased MLC activity thus allows MLC-phosphatase to promote relaxation of the smooth muscle. Clinically, while the cardiovascular effect of caffeine is debatable, the increased cAMP levels may play a part in vasodilation properties in cardiovascular health; however, further research is necessary.Rolipram inhibits PDE4 to treat depression, various inflammatory pathways, and impacts memory and intelligence. However, strong side effects follow its use.
Chronic inflammatory diseases can be treated with S-adenosylmethionine (SAM), a PDE4B inhibitor.
Pentoxifylline works as an "immunosuppressant, has anti-fibrotic activity, and improves hemodynamics."
A PDE3 inhibitor, cilostazol, is an anti-inflammatory medication that also has the potential to "inhibit platelet aggregation" and can promote vasodilation.
Studies further show cAMP and PKA may even play a vital role in mood disorders. Bipolar patients demonstrate higher PKA activity in comparison to patients with unipolar depression.  Animal studies demonstrate that stress may play a potential regulating factor with cAMP and PKA regulation. One study found that a rise in stress decreases interaction between cAMP and PKA in the cortex and hippocampus in rats with corticosterone treatment; however, upon removing the adrenal gland, cAMP and PKA binding activity increased.
In the heart, cAMP plays a vital role in regulating myocardial contraction and relaxation. cAMP, produced from beta-adrenergic stimulation, interacts with PKA and induces a positive inotropic effect on the heart by coupling with the phosphorylation of L-type Calcium channels and ryanodine receptors  When PKA phosphorylates phospholamban, it causes the reuptake of calcium into the sarcoplasmic reticulum in the myocytes causing cardiac muscle relaxation. cAMP involvement in the heart has become a point of focus in understanding the complexity of the cAMP pathway interactions.
Because cAMP is a ubiquitous effector across many biological systems, understanding the organization of its signaling pathway becomes important. Besides temporal control, studies reveal cAMP signal transduction is regulated by a spatial control which is compartmentalization of molecular components of a system that are confined to a specific subcellular location and found in variability of isoforms.  Studying the organization of cAMP transduction pathways may result in a better understanding of cAMP signaling and further create opportunities for therapeutic interventions.
|||Serezani CH,Ballinger MN,Aronoff DM,Peters-Golden M, Cyclic AMP: master regulator of innate immune cell function. American journal of respiratory cell and molecular biology. 2008 Aug [PubMed PMID: 18323530]|
|||Zaccolo M, cAMP signal transduction in the heart: understanding spatial control for the development of novel therapeutic strategies. British journal of pharmacology. 2009 Sep [PubMed PMID: 19371331]|
|||Kamenetsky M,Middelhaufe S,Bank EM,Levin LR,Buck J,Steegborn C, Molecular details of cAMP generation in mammalian cells: a tale of two systems. Journal of molecular biology. 2006 Sep 29 [PubMed PMID: 16934836]|
|||Yan K,Gao LN,Cui YL,Zhang Y,Zhou X, The cyclic AMP signaling pathway: Exploring targets for successful drug discovery (Review). Molecular medicine reports. 2016 May [PubMed PMID: 27035868]|
|||Chen H,Wild C,Zhou X,Ye N,Cheng X,Zhou J, Recent advances in the discovery of small molecules targeting exchange proteins directly activated by cAMP (EPAC). Journal of medicinal chemistry. 2014 May 8 [PubMed PMID: 24256330]|
|||Dwivedi Y,Pandey GN, Adenylyl cyclase-cyclicAMP signaling in mood disorders: role of the crucial phosphorylating enzyme protein kinase A. Neuropsychiatric disease and treatment. 2008 Feb [PubMed PMID: 18728821]|
|||Cheng X,Ji Z,Tsalkova T,Mei F, Epac and PKA: a tale of two intracellular cAMP receptors. Acta biochimica et biophysica Sinica. 2008 Jul [PubMed PMID: 18604457]|
|||Almahariq M,Mei FC,Cheng X, Cyclic AMP sensor EPAC proteins and energy homeostasis. Trends in endocrinology and metabolism: TEM. 2014 Feb [PubMed PMID: 24231725]|
|||Echeverri D,Montes FR,Cabrera M,Galán A,Prieto A, Caffeine's Vascular Mechanisms of Action. International journal of vascular medicine. 2010 [PubMed PMID: 21188209]|
|||Zaccolo M, Spatial control of cAMP signalling in health and disease. Current opinion in pharmacology. 2011 Dec [PubMed PMID: 22000603]|