:Cyclic adenosine monophosphate

Earl Sutherland of Vanderbilt University won a Nobel Prize in Physiology or Medicine in 1971 "for his discoveries concerning the mechanisms of the action of hormones", especially epinephrine, via second messengers (such as cyclic adenosine monophosphate, cyclic AMP).

The synthesis of cAMP is stimulated by trophic hormones that bind to receptors on the cell surface. cAMP levels reach maximal levels within minutes and decrease gradually over an hour in cultured cells.{{cite journal |vauthors=Hanukoglu I, Feuchtwanger R, Hanukoglu A |title=Mechanism of corticotropin and cAMP induction of mitochondrial cytochrome P450 system enzymes in adrenal cortex cells |journal=J Biol Chem |volume=265 |issue=33 |pages=20602–8 |date=November 1990 |pmid=2173715 |doi=10.1016/S0021-9258(17)30545-8 |url=|doi-access=free }}

Cyclic AMP is synthesized from ATP by adenylate cyclase located on the inner side of the plasma membrane and anchored at various locations in the interior of the cell.{{cite journal | vauthors = Rahman N, Buck J, Levin LR | date = November 2013 | title = pH sensing via bicarbonate-regulated "soluble" adenylate cyclase (sAC) | journal = Front Physiol | volume = 4 | page = 343 | pmid = 24324443 | pmc=3838963 | doi=10.3389/fphys.2013.00343| doi-access = free }} Adenylate cyclase is activated by a range of signaling molecules through the activation of adenylate cyclase stimulatory G (G_s)-protein-coupled receptors. Adenylate cyclase is inhibited by agonists of adenylate cyclase inhibitory G (G_i)-protein-coupled receptors. Liver adenylate cyclase responds more strongly to glucagon, and muscle adenylate cyclase responds more strongly to adrenaline.

cAMP decomposition into AMP is catalyzed by the enzyme phosphodiesterase.

cAMP is a second messenger, used for intracellular signal transduction, such as transferring into cells the effects of hormones like glucagon and adrenaline, which cannot pass through the plasma membrane. It is also involved in the activation of protein kinases. In addition, cAMP binds to and regulates the function of ion channels such as the HCN channels and a few other cyclic nucleotide-binding proteins such as Epac1 and RAPGEF2.

{{Main|function of cAMP-dependent protein kinase}}

cAMP is associated with kinases function in several biochemical processes, including the regulation of glycogen, sugar, and lipid metabolism.{{cite journal |vauthors=Ali ES, Hua J, Wilson CH, Tallis GA, Zhou FH, Rychkov GY, Barritt GJ |title=The glucagon-like peptide-1 analogue exendin-4 reverses impaired intracellular Ca2+ signalling in steatotic hepatocytes |journal=Biochimica et Biophysica Acta (BBA) - Molecular Cell Research |doi=10.1016/j.bbamcr.2016.05.006 |pmid=27178543 |volume=1863 |year=2016 |issue=9 |pages=2135–46|doi-access=free }}

In eukaryotes, cyclic AMP works by activating protein kinase A (PKA, or cAMP-dependent protein kinase). PKA is normally inactive as a tetrameric holoenzyme, consisting of two catalytic and two regulatory units (C₂R₂), with the regulatory units blocking the catalytic centers of the catalytic units.

Cyclic AMP binds to specific locations on the regulatory units of the protein kinase, and causes dissociation between the regulatory and catalytic subunits, thus enabling those catalytic units to phosphorylate substrate proteins.

The active subunits catalyze the transfer of phosphate from ATP to specific serine or threonine residues of protein substrates. The phosphorylated proteins may act directly on the cell's ion channels, or may become activated or inhibited enzymes. Protein kinase A can also phosphorylate specific proteins that bind to promoter regions of DNA, causing increases in transcription. Not all protein kinases respond to cAMP. Several classes of protein kinases, including protein kinase C, are not cAMP-dependent.

Further effects mainly depend on cAMP-dependent protein kinase, which vary based on the type of cell.

Still, there are some minor PKA-independent functions of cAMP, e.g., activation of calcium channels, providing a minor pathway by which growth hormone-releasing hormone causes a release of growth hormone.

However, the view that the majority of the effects of cAMP are controlled by PKA is an outdated one. In 1998 a family of cAMP-sensitive proteins with guanine nucleotide exchange factor (GEF) activity was discovered. These are termed Exchange proteins activated by cAMP (Epac) and the family comprises Epac1 and Epac2.{{cite journal|last1=Bos|first1=Johannes L.|title=Epac proteins: multi-purpose cAMP targets|journal=Trends in Biochemical Sciences|date=December 2006|volume=31|issue=12|pages=680–686|doi=10.1016/j.tibs.2006.10.002|pmid=17084085}} The mechanism of activation is similar to that of PKA: the GEF domain is usually masked by the N-terminal region containing the cAMP binding domain. When cAMP binds, the domain dissociates and exposes the now-active GEF domain, allowing Epac to activate small Ras-like GTPase proteins, such as Rap1.

{{See also|Fungal behavior}}

In the species Dictyostelium discoideum, cAMP acts outside the cell as a secreted signal. The chemotactic aggregation of cells is organized by periodic waves of cAMP that propagate between cells over distances as large as several centimetres. The waves are the result of a regulated production and secretion of extracellular cAMP and a spontaneous biological oscillator that initiates the waves at centers of territories.{{Cite book|last=Anderson|first=Peter A. V.|url=https://books.google.com/books?id=vEYGCAAAQBAJ&q=In+the+species+Dictyostelium+discoideum,+cAMP+acts+outside+the+cell+as+a+secreted+signal.+The+chemotactic+aggregation+of+cells+is+organized+by+periodic+waves+of+cAMP+that+propagate+between+cells+over+distances+as+large+as+several+centimetres.+The+waves+are+the+result+of+a+regulated+production+and+secretion+of+extracellular+cAMP+and+a+spontaneous+biological+oscillator+that+initiates+the+waves+at+centers+of+territories|title=Evolution of the First Nervous Systems|date=2013-11-11|publisher=Springer Science & Business Media|isbn=978-1-4899-0921-3|language=en}}

In bacteria, the level of cAMP varies depending on the medium used for growth. In particular, cAMP is low when glucose is the carbon source. This occurs through inhibition of the cAMP-producing enzyme, adenylate cyclase, as a side-effect of glucose transport into the cell. The transcription factor cAMP receptor protein (CRP) also called CAP (catabolite gene activator protein) forms a complex with cAMP and thereby is activated to bind to DNA. CRP-cAMP increases expression of a large number of genes, including some encoding enzymes that can supply energy independent of glucose.

cAMP, for example, is involved in the positive regulation of the lac operon. In an environment with a low glucose concentration, cAMP accumulates and binds to the allosteric site on CRP (cAMP receptor protein), a transcription activator protein. The protein assumes its active shape and binds to a specific site upstream of the lac promoter, making it easier for RNA polymerase to bind to the adjacent promoter to start transcription of the lac operon, increasing the rate of lac operon transcription. With a high glucose concentration, the cAMP concentration decreases, and the CRP disengages from the lac operon.

Since cyclic AMP is a second messenger and plays vital role in cell signalling, it has been implicated in various disorders but not restricted to the roles given below:

Some research has suggested that a deregulation of cAMP pathways and an aberrant activation of cAMP-controlled genes is linked to the growth of some cancers.{{cite journal| url = http://cancerres.aacrjournals.org/cgi/content/full/64/4/1338| title = American Association for Cancer Research (cAMP-responsive Genes and Tumor Progression)| journal = Cancer Research| date = 15 February 2004| volume = 64| issue = 4| pages = 1338–1346| doi = 10.1158/0008-5472.CAN-03-2089| last1 = Abramovitch| first1 = Rinat| last2 = Tavor| first2 = Einat| last3 = Jacob-Hirsch| first3 = Jasmine| last4 = Zeira| first4 = Evelyne| last5 = Amariglio| first5 = Ninette| last6 = Pappo| first6 = Orit| last7 = Rechavi| first7 = Gideon| last8 = Galun| first8 = Eithan| last9 = Honigman| first9 = Alik| pmid = 14973073| s2cid = 14047485}}{{cite journal| url = http://cancerres.aacrjournals.org/cgi/content/abstract/66/19/9483| title = American Association for Cancer Research (cAMP Dysregulation and Melonoma)| journal = Cancer Research| date = October 2006| volume = 66| issue = 19| pages = 9483–9491| doi = 10.1158/0008-5472.CAN-05-4227| last1 = Dumaz| first1 = Nicolas| last2 = Hayward| first2 = Robert| last3 = Martin| first3 = Jan| last4 = Ogilvie| first4 = Lesley| last5 = Hedley| first5 = Douglas| last6 = Curtin| first6 = John A.| last7 = Bastian| first7 = Boris C.| last8 = Springer| first8 = Caroline| last9 = Marais| first9 = Richard| pmid = 17018604| doi-access = free}}{{cite journal| url = http://clincancerres.aacrjournals.org/cgi/content/abstract/2/1/201| title = American Association for Cancer Research (cAMP-binding Proteins' Presence in Tumors)| journal = Clinical Cancer Research| date = January 1996| volume = 2| issue = 1| pages = 201–206| last1 = Simpson| first1 = B. J.| last2 = Ramage| first2 = A. D.| last3 = Hulme| first3 = M. J.| last4 = Burns| first4 = D. J.| last5 = Katsaros| first5 = D.| last6 = Langdon| first6 = S. P.| last7 = Miller| first7 = W. R.}}

Research suggests that cAMP affects the function of higher-order thinking in the prefrontal cortex through its regulation of ion channels called hyperpolarization-activated cyclic nucleotide-gated channels (HCN). HCN channels will open when exposed to cAMP. Once the HCN channel is open, the electrical activity within the neuron is disrupted and the cell becomes less responsive. This interferes with the function of the prefrontal cortex in working memory tasks. Inhibition of cAMP has been observed to improve spatial working memory.{{cite web| last1 = Arnsten| first1 = Amy| last2 = McCormick| first2 = David| title = Cyclic AMP, a molecule linked to stress, also plays a role in memory loss| date = 2007| url = https://medicine.yale.edu/news/yale-medicine-magazine/article/cyclic-amp-a-molecule-linked-to-stress-also/}}{{cite journal| doi = 10.1016/j.cell.2007.03.015| issn = 00928674| volume = 129| issue = 2| pages = 397–410| last1 = Wang| first1 = Min| last2 = Ramos| first2 = Brian P.| last3 = Paspalas| first3 = Constantinos D.| last4 = Shu| first4 = Yousheng| last5 = Simen| first5 = Arthur| last6 = Duque| first6 = Alvaro| last7 = Vijayraghavan| first7 = Susheel| last8 = Brennan| first8 = Avis| last9 = Dudley| first9 = Anne| last10 = Nou| first10 = Eric| last11 = Mazer| first11 = James A.| last12 = McCormick| first12 = David A.| last13 = Arnsten| first13 = Amy F.T.| title = α2A-Adrenoceptors Strengthen Working Memory Networks by Inhibiting cAMP-HCN Channel Signaling in Prefrontal Cortex| journal = Cell| access-date = 2025-03-03| date = April 2007 | url = https://linkinghub.elsevier.com/retrieve/pii/S0092867407003443| doi-access = free}}

cAMP is involved in activation of trigeminocervical system leading to neurogenic inflammation and causing migraine. {{cite journal |last1=Segatto |first1=Marco |title=Neurogenic Inflammation: The Participant in Migraine and Recent Advancements in Translational Research |journal=Biomedicines |year=2021 |volume=10 |issue=1 |page=76 |doi=10.3390/biomedicines10010076 |pmid=35052756 |pmc=8773152 |doi-access=free }}

Disrupted functioning of cAMP has been noted as one of the mechanisms of several bacterial exotoxins.

They can be subgrouped into two distinct categories:{{cite journal |last1=Kather |first1=H |last2=Aktories |first2=K |date=November 15, 1983 |title=cAMP-System und bakterielle Toxine [The cAMP system and bacterial toxins] |url=https://pubmed.ncbi.nlm.nih.gov/6317939/ |journal=Klin Wochenschr |volume= 61|issue= 22|pages= 1109–1114| pmid=6317939 |doi=10.1007/BF01530837 |s2cid=33162709 |access-date=February 26, 2022}}

• Toxins that interfere with enzymes ADP-ribosyl-transferases, and
• invasive adenylate cyclases.

{{Main article|Cholera toxin}}

• Cholera toxin is an AB toxin that has five B subunints and one A subunit. The toxin acts by the following mechanism: First, the B subunit ring of the cholera toxin binds to GM1 gangliosides on the surface of target cells. If a cell lacks GM1 the toxin most likely binds to other types of glycans, such as Lewis Y and Lewis X, attached to proteins instead of lipids.{{cite news |url=https://elifesciences.org/content/4/e09545 |title=Fucosylation and protein glycosylation create functional receptors for cholera toxin |author=Amberlyn M Wands |author2=Akiko Fujita |journal=eLife | date=October 2015 |volume=4 |doi=10.7554/eLife.09545 |doi-access=free }}Cervin J, Wands AM, Casselbrant A, Wu H, Krishnamurthy S, Cvjetkovic A, et al. (2018) GM1 ganglioside-independent intoxication by Cholera toxin. PLoS Pathog 14(2): e1006862. https://doi.org/10.1371/journal.ppat.1006862{{Cite journal |last=Wands |first=Amberlyn M. |last2=Cervin |first2=Jakob |last3=Huang |first3=He |last4=Zhang |first4=Ye |last5=Youn |first5=Gyusaang |last6=Brautigam |first6=Chad A. |last7=Matson Dzebo |first7=Maria |last8=Björklund |first8=Per |last9=Wallenius |first9=Ville |last10=Bright |first10=Danielle K. |last11=Bennett |first11=Clay S. |last12=Wittung-Stafshede |first12=Pernilla |last13=Sampson |first13=Nicole S. |last14=Yrlid |first14=Ulf |last15=Kohler |first15=Jennifer J. |date=2018-05-11 |title=Fucosylated Molecules Competitively Interfere with Cholera Toxin Binding to Host Cells |url=https://pubs.acs.org/doi/10.1021/acsinfecdis.7b00085 |journal=ACS Infectious Diseases |language=en |volume=4 |issue=5 |pages=758–770 |doi=10.1021/acsinfecdis.7b00085 |issn=2373-8227 |pmc=5948155 |pmid=29411974}}

Forskolin is commonly used as a tool in biochemistry to raise levels of cAMP in the study and research of cell physiology.

{{cite journal|last1=Alasbahi|first1=RH|last2=Melzig|first2=MF|title=Forskolin and derivatives as tools for studying the role of cAMP.|journal=Die Pharmazie|date=January 2012|volume=67|issue=1|pages=5–13|pmid=22393824}}

• Cyclic guanosine monophosphate (cGMP)
• 8-Bromoadenosine 3',5'-cyclic monophosphate (8-Br-cAMP)
• Acrasin specific to chemotactic use in Dictyostelium discoideum.
• phosphodiesterase 4 (PDE 4) which degrades cAMP

{{Intracellular signaling peptides and proteins}}

{{Nucleobases, nucleosides, and nucleotides}}

{{DEFAULTSORT:Cyclic Adenosine Monophosphate}}

Category:Nucleotides

Category:Signal transduction

Category:Cell signaling

Category:Cyclic nucleotides

Category:Second messenger system