Cyclic adenosine monophosphate is a second messenger important in many biological processes.
cAMP is derived from adenosine triphosphate and used for intracellular signal transduction
in many different organisms, conveying the cAMP-dependent pathway.
History Earl Sutherland of Case Western Reserve 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.
Synthesis and decomposition cAMP is synthesized from ATP by adenylyl cyclase
located on the inner side of the plasma membrane and anchored at various locations in the interior
of the cell. Adenylyl Cyclase is activated by a range of signaling molecules through
the activation of adenylyl cyclase stimulatory G-protein-coupled receptors. Adenylyl Cyclase
is inhibited by agonists of adenylyl cyclase inhibitory G-protein-coupled receptors. Liver
adenylyl cyclase responds more strongly to glucagon, and muscle adenylyl cyclase responds
more strongly to adrenaline. cAMP decomposition into AMP is catalyzed by
the enzyme phosphodiesterase. Functions
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 involved in the activation of protein kinases and regulates
the effects of adrenaline and glucagon. cAMP also 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. Role of cAMP in eukaryotic cells
cAMP and its associated kinases function in several biochemical processes, including the
regulation of glycogen, sugar, and lipid metabolism. In eukaryotes, cyclic AMP works by activating
protein kinase A. PKA is normally inactive as a tetrameric holoenzyme, consisting of
two catalytic and two regulatory units, 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 increased expression of specific genes. 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 activity was discovered. These are
termed Exchange proteins activated by cAMP and the family comprises Epac1 and Epac2.
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. Additional role of secreted cAMP in social
amoebas
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. Role of cAMP in bacteria
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 also called CAP 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
of a low glucose concentration, cAMP accumulates and binds to the allosteric site on CRP, 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. Pathology
Role of cAMP in human carcinoma 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. Role of cAMP in prefrontal cortex disorders
Recent 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. When cAMP stimulates the HCN, the channels open, closing
the brain cell to communication and thus interfering with the function of the prefrontal cortex.
This research, especially the cognitive deficits in age-related illnesses and ADHD, is of interest
to researchers studying the brain. See also
Cyclic guanosine monophosphate 8-Bromoadenosine 3',5'-cyclic monophosphate
Acrasin specific to chemotactic use in Dictyostelium discoideum.
phosphodiesterase 4 which degrades cAMP References
^ Rahman N, Buck J, Levin LR. pH sensing via bicarbonate-regulated "soluble" adenylyl cyclase
Front Physiol. 2013 Nov 25;4:343. eCollection 2013. Review. PMID 4324443
^ GeneGlobe -> GHRH Signaling Retrieved on May 31, 2009
^ American Association for Cancer Research ^ American Association for Cancer Research
^ American Association for Cancer Research ^ ScienceDaily ::Brain Networks Strengthened
By Closing Ion Channels, Research Could Lead To ADHD Treatment
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