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Cyclic AMP signalling pathway

Cyclic AMP is a ubiquitous second messenger that regulates a multitude of cellular


responses. Cyclic AMP formation usually depends upon the activation of G-protein-coupled
receptors (GPCRs) that use heterotrimeric G proteins to activate the amplifier adenylyl cyclase
(AC).
The cAMP signal transduction contains 5 main characters:
1.Stimulative hormonereceptor (Rs) or inhibitory hormone receptor (Ri),
2.Stimulative regulative G-protein (Gs) or inhibitory regulative G-protein (Gi)
3. Adenyl cyclase
4. Protein kinase A or PKA
5. cAMP phosphodiesterase

Stimulative hormone receptor (Rs) is a receptor that can bind with stimulative signal molecules,
while inhibitory hormone (Ri) is a receptor that can bind with inhibitory signal molecules.
Stimulative regulative G-protein is a G protein-linked to stimulative hormone receptor (Rs) and
its subunit upon activation could stimulate the activity of an enzyme or other intracellular
metabolism. On the contrary, inhibitory regulative G-protein is linked to an inhibitory hormone
receptor and its subunit upon activation could inhibit the activity of an enzyme or other
intracellular metabolism.
Cyclic AMP formation
The formation of cyclic AMP can be activated by a very large number of cell stimuli, mainly
neurotransmitters and hormones. All these stimuli are detected by G-protein-coupled receptors
(GPCRs) that use heterotrimeric G proteins , which are the transducers that are responsible for
either activating or inhibiting the enzyme adenylyl cyclase (AC). In the case of AC stimulation,
the external stimulus binds to the GPCR that functions as a guanine nucleotide exchange factor
(GEF) to replace GDP with GTP, which dissociates the heterotrimeric complex into their G
and G subunits. The GSGTP complex activates AC, whereas GiGTP inhibits AC. The G
subunits have GTPase activity that hydrolyses GTP to GDP, thus terminating their effects on
AC. The endogenous GTPase of GSGTP is inhibited by cholera toxin and this causes the
persistent activation of the intestinal fluid secretion that results in the symptoms of cholera.
Adenylyl cyclase (AC)

The large cytoplasmic domains C1 and C2 contain the catalytic region, form a heterodimer and
co-operate with each other to convert ATP into cyclic AMP.
Cyclic AMP signalling effectors
Cyclic AMP is a highly versatile intracellular messenger capable of activating a number of
different effectors.
There are three main effectors of cAMP:

i.
ii.
iii.

exchange proteins activated by cyclic AMP (EPACs)


cyclic nucleotide-gated channels (CNGCs)
Protein kinase A (PKA) .

Exchange proteins activated by cyclic AMP (EPACs)


One of the functions of EPACs is to activate Rap1 and Rap2B , which have many functions,
many of which are related to controlling actin dynamics. In addition, the EPAC/Rap pathway
can activate phospholipase C (PLC) and this mechanism has been implicated in the control
of autophagy.
cyclic nucleotide-gated (CNGCs)
It plays a particularly important role in the sensory systems responsible for smell and taste.
Protein kinase A (PKA)
Many of the actions of cyclic AMP are carried out by protein kinase A (PKA), which
phosphorylates specific sites on downstream effector. PKA is composed of two regulatory (R)
subunits and two catalytic (C) subunits. The way in which cyclic AMP activates PKA is to bind
to the R subunits, which then enables the C subunits to phosphorylate a wide range of different
substrates. Of the two types of PKA, protein kinase A (PKA) I is found mainly free in the
cytoplasm and has a high affinity for cyclic AMP, whereas protein kinase A (PKA) II has a
much more precise location by being coupled to the A-kinase-anchoring proteins (AKAPs).
The AKAPs are the scaffolding proteins that function in the spatial organization of signalling
pathways by bringing PKA into contact with its many substrates.
Protein kinase A (PKA) I
Type I protein kinase A (PKA) associates with the RI isoforms. As for all isoforms, the R
subunits form dimers through their N-terminal dimerization/docking domains. In addition to
holding two R subunits together, this N-terminal region is also responsible for docking to the
A-kinase-anchoring proteins (AKAPs), as occurs for PKA II. However, the RI isoforms have a
very low affinity for the AKAPs and are thus mainly soluble. Cyclic AMP acts by binding to
the tandem cyclic AMP-binding domains to release active C subunits that then phosphorylate

specific substrates. Since the RI subunits have a higher cyclic AMP-binding affinity, PKA I will
be able to respond to the lower cyclic AMP concentrations found globally within the bulk
cytoplasm.
Protein kinase A (PKA) II
A characteristic feature of Type II protein kinase A (PKA) is that the regulatory dimer is made
up of RII subunits. Since this RII subunit has a much higher affinity for the A-kinase-anchoring
proteins (AKAPs), PKA II is usually docked to this scaffolding protein and thus has a much
more precise localization to specific cellular targets.
The substrates phosphorylated by cyclic AMP fall into two main groups:
i.
ii.

the cyclic AMP substrates that regulate specific cellular processes and
the cyclic AMP substrates that are components of other signalling systems.

Cyclic AMP substrates that regulate specific cellular processes:

In neurons, cyclic AMP acts through PKA to phosphorylate Ser-845 on the AMPA
receptor

Cyclic AMP acting through PKA stimulates the fructose-2,6-bisphosphatase component


to lower the level of fructose 2,6-bisphosphate, which reduces glycolysis and promotes
gluconeogenesis.

In insulin-secreting -cells, the salt-inducible kinase 2 (SIK2) that phosphorylates


transducer of regulated cyclic AMP response element-binding protein (TORC) is
inhibited by a cyclic AMP/PKA-dependent phosphorylation.

PKA phosphorylates the hormone-sensitive lipase (HLS) that initiates the hydrolysis of
triacylglycerol to free fatty acids and glycerol in both white fat cells and in brown fat
cells.

PKA phosphorylates the phosphorylase kinase that converts inactive phosphorylase b


into active phosphorylase a in skeletal muscle and in liver cells.

PKA activates the transcription factor cyclic AMP response element-binding protein
(CREB). This activation is a critical event in the induction of gluconeogenesis in liver
cells.

PKA inhibits the salt-inducible kinase 2 (SIK2) that normally acts to phosphorylate
TORC2, thereby preventing it from entering the nucleus to facilitate the activity of
CREB.

PKA phosphorylates inhibitor 1 (I1), which assists the protein phosphorylation process
by inactivating protein phosphatase 1 (PP1).

PKA contributes to the translocation and fusion of vesicles with the apical membrane
during the onset of acid secretion by parietal cells.

PKA phosphorylates the regulatory (R) domain on the cystic fibrosis transmembrane
conductance regulator (CFTR) to enable it to function as an anion channel.

In the small intestine, PKA phosphorylates the cystic fibrosis transmembrane


conductance regulator (CFTR)channel that is responsible for activating fluid secretion.
Uncontrolled activation of cyclic AMP formation by cholera toxin results in cholera.

In kidney collecting ducts, cyclic AMP acts through PKA to phosphorylate Ser-256 on
the C-terminal cytoplasmic tail of aquaporin 2 (AQP2), enabling this water channel to
fuse with the apical membrane to allow water to enter the cell.

In blood platelets, cyclic AMP activates the phosphorylation of vasodilator-stimulated


phosphoprotein (VASP), which is a member of the Ena/vasodilator-stimulated
phosphoprotein (VASP) family resulting in a decrease in the actin-dependent processes
associated with clotting.

Cyclic AMP substrates that are components of other signalling systems:

Phosphorylation of the cyclic GMP phosphodiesterase PDE1A by PKA results in a


decrease in its sensitivity to Ca2+ activation.

Entry of Ca2+ through the L-type CaV1.1 channel (Module 3: Figure CaV1.1 L-type
channel) and the L-type CaV1.2 channel is enhanced through PKA-dependent
phosphorylation.

PKA-dependent phosphorylation of dopamine- and cyclic AMP-regulated


phosphoprotein of apparent molecular mass 32 kDa (DARPP-32) functions as a
molecular switch to regulate the activity of protein phosphatase 1 (PP1).

The ryanodine receptor 2 (RYR2) is modulated by phosphorylation through PKA,


which is associated with the cytoplasmic head through an AKAP.

Sarco/endo-plasmic reticulum Ca2+-ATPase 2a (SERCA2a) increases its Ca2+-pumping


activity when the inhibitory effect of phospholamban (PLN) is removed following its
phosphorylation by PKA on Ser-16.

Cyclic AMP signalling functions

The cyclic AMP signalling pathway functions in the control of a wide range of cellular
processes:

Cyclic AMP suppresses spontaneous Ca2+ oscillations during oocyte maturation.

Cyclic AMP has a potent anti-inflammatory action by inhibiting the activity of


macrophages and mast cells.

Melanocortin 4 receptors (MC4Rs) on second-order neurons use the cyclic AMP


signalling pathway to induce the hypothalamic transcription factor Single-minded 1
(Sim1) to decrease food intake and weight loss.

Cyclic AMP mediates the action of lipolytic hormones in white fat cells by stimulating a
hormone-sensitive lipase.

Heat production by brown fat cells is controlled by noradrenaline acting through cyclic
AMP.

The phosphorylation of dopamine- and cyclic AMP-regulated phosphoprotein of


apparent molecular mass 32 kDa (DARPP-32) co-ordinates the activity of the dopamine
and glutamate signalling pathways in medium spiny neurons.

Adrenaline-induced glycogenolysis in skeletal muscle cells depends upon a cyclic


AMP-dependent phosphorylation of phosphorylase kinase.

Activation of the cyclic AMP-dependent transcription factor cyclic AMP response


element-binding protein (CREB) contributes to the regulation of glucagon biosynthesis
in glucagon-secreting -cells.

Cyclic AMP hydrolysis


There are two OFF reactions of the cyclic AMP signalling pathway, cyclic AMP efflux from the
cell and cyclic AMP hydrolysis. The latter is carried out by a family of
phosphodiesterase enzymes that hydrolyse cyclic AMP to AMP.
Cyclic AMP efflux
There are two OFF reactions for the cyclic AMP signalling pathway, cyclic AMP
hydrolysis and cyclic AMP efflux from the cell.
The latter is carried out by ABCC4, which is one of the ATP-binding cassette (ABC)
transporters.