CYCLIC ADENOSINE MONOPHOSPHATE

Cyclic adenosine monophosphate (cAMP, cyclic AMP, or 3',5'-cyclic adenosine

monophosphate) is a second messengerimportant in many biological processes.
cAMP is derived from adenosine triphosphate (ATP) and used for intracellular signal
transduction in many different organisms, conveying the cAMP-dependent pathway.
Synthesis and decomposition
cAMP 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. Adenylate cyclase is activated by a range of signaling molecules through the
activation of adenylate cyclase stimulatory G (Gs)-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 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.
FUNCTIONS
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, or cAMPdependent
protein
kinase).
PKA
is
normally
inactive
as
a
tetrameric holoenzyme, consisting of twocatalytic 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
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 hormonecauses 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. 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 (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 of 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.
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 higherorder thinking in the prefrontal cortex through its regulation of ion channels
called hyperpolarization-activated cyclic nucleotide-gated channels (HCN).
When cAMP stimulates the HCN, the channels open, closing the brain cell to
communication and thus interfering with the function of theprefrontal cortex.
This research, especially the cognitive deficits in age-related illnesses and
ADHD, is of interest to researchers studying the brain.