In the field of
molecular biology
Molecular biology is a branch of biology that seeks to understand the molecule, molecular basis of biological activity in and between Cell (biology), cells, including biomolecule, biomolecular synthesis, modification, mechanisms, and interactio ...
, the cAMP-dependent pathway, also known as the
adenylyl cyclase
Adenylate cyclase (EC 4.6.1.1, also commonly known as adenyl cyclase and adenylyl cyclase, abbreviated AC) is an enzyme with systematic name ATP diphosphate-lyase (cyclizing; 3′,5′-cyclic-AMP-forming). It catalyzes the following reaction:
:A ...
pathway, is a
G protein-coupled receptor
G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily related ...
-triggered
signaling cascade used in
cell communication.
Discovery
cAMP was discovered by
Earl Sutherland and Ted Rall in the mid 1950s. cAMP is considered a secondary messenger along with
Ca2+. Sutherland won the Nobel Prize in 1971 for his discovery of the mechanism of action of epinephrine in glycogenolysis, that requires cAMP as secondary messenger.
Mechanism
G protein-coupled receptors
G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large protein family, group of evoluti ...
(GPCRs) are a large family of
integral membrane protein
An integral, or intrinsic, membrane protein (IMP) is a type of membrane protein that is permanently attached to the biological membrane. All transmembrane proteins can be classified as IMPs, but not all IMPs are transmembrane proteins. IMPs comp ...
s that respond to a variety of extracellular stimuli. Each GPCR binds to and is activated by a specific
ligand
In coordination chemistry, a ligand is an ion or molecule with a functional group that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's el ...
stimulus that ranges in size from small molecule
catecholamine
A catecholamine (; abbreviated CA), most typically a 3,4-dihydroxyphenethylamine, is a monoamine neurotransmitter, an organic compound that has a catechol (benzene with two hydroxyl side groups next to each other) and a side-chain amine.
Cate ...
s, lipids, or
neurotransmitter
A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a Chemical synapse, synapse. The cell receiving the signal, or target cell, may be another neuron, but could also be a gland or muscle cell.
Neurotra ...
s to large protein hormones. When a GPCR is activated by its extracellular ligand, a conformational change is induced in the receptor that is transmitted to an attached intracellular
heterotrimeric G protein complex. The
Gs alpha subunit of the stimulated G protein complex exchanges
GDP for
GTP and is released from the complex.
In a cAMP-dependent pathway, the activated G
s alpha subunit binds to and activates an enzyme called
adenylyl cyclase
Adenylate cyclase (EC 4.6.1.1, also commonly known as adenyl cyclase and adenylyl cyclase, abbreviated AC) is an enzyme with systematic name ATP diphosphate-lyase (cyclizing; 3′,5′-cyclic-AMP-forming). It catalyzes the following reaction:
:A ...
, which, in turn, catalyzes the conversion of
ATP into
cyclic adenosine monophosphate
Cyclic adenosine monophosphate (cAMP, cyclic AMP, or 3',5'-cyclic adenosine monophosphate) is a second messenger, or cellular signal occurring within cells, that is important in many biological processes. cAMP is a derivative of adenosine tri ...
(cAMP).
Increases in concentration of the
second messenger
Second messengers are intracellular signaling molecules released by the cell in response to exposure to extracellular signaling molecules—the first messengers. (Intercellular signals, a non-local form of cell signaling, encompassing both first m ...
cAMP may lead to the activation of
*
cyclic nucleotide-gated ion channels
* exchange proteins activated by cAMP (EPAC)
such as
RAPGEF3
* popeye domain containing proteins (Popdc)
* an enzyme called
protein kinase A
In cell biology, protein kinase A (PKA) is a family of serine-threonine kinases whose activity is dependent on cellular levels of cyclic AMP (cAMP). PKA is also known as cAMP-dependent protein kinase (). PKA has several functions in the cell, in ...
(PKA).
The PKA enzyme is also known as cAMP-dependent enzyme because it gets activated only if cAMP is present. Once PKA is activated, it
phosphorylates a number of other proteins including:
* enzymes that convert
glycogen
Glycogen is a multibranched polysaccharide of glucose that serves as a form of energy storage in animals, fungi, and bacteria. It is the main storage form of glucose in the human body.
Glycogen functions as one of three regularly used forms ...
into
glucose
Glucose is a sugar with the Chemical formula#Molecular formula, molecular formula , which is often abbreviated as Glc. It is overall the most abundant monosaccharide, a subcategory of carbohydrates. It is mainly made by plants and most algae d ...
* enzymes that promote muscle contraction in the heart leading to an increase in heart rate
*
transcription factor
In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription (genetics), transcription of genetics, genetic information from DNA to messenger RNA, by binding t ...
s, which regulate gene expression
* also phosphorylate AMPA receptors
Specificity of signaling between a GPCR and its ultimate molecular target through a cAMP-dependent pathway may be achieved through formation of a multiprotein complex that includes the GPCR, adenylyl cyclase, and the effector protein.
Importance
In humans, cAMP works by activating protein kinase A (PKA,
cAMP-dependent protein kinase), one of the first few kinases discovered. It has four sub-units two catalytic and two regulatory. cAMP binds to the regulatory sub-units. It causes them to break apart from the catalytic sub-units. The catalytic sub-units make their way in to the nucleus to influence transcription. Further effects mainly depend on
cAMP-dependent protein kinase, which vary based on the type of cell.
cAMP-dependent pathway is necessary for many living organisms and life processes. Many different cell responses are mediated by cAMP; these include increase in heart rate, cortisol secretion, and breakdown of glycogen and fat. cAMP is essential for the maintenance of memory in the brain, relaxation in the heart, and water absorbed in the kidney.
This pathway can
activate enzymes and
regulate gene expression. The activation of preexisting enzymes is a much faster process, whereas regulation of gene expression is much longer and can take up to hours. The cAMP pathway is studied through loss of function (inhibition) and gain of function (increase) of cAMP.
If cAMP-dependent pathway is not controlled, it can ultimately lead to hyper-proliferation, which may contribute to the development and/or progression of
cancer
Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...
.
Activation
Activated GPCRs cause a conformational change in the attached G protein complex, which results in the G
s alpha subunit's exchanging GDP for GTP and separation from the beta and gamma subunits. The G
s alpha subunit, in turn, activates adenylyl cyclase, which quickly converts ATP into cAMP. This leads to the activation of the cAMP-dependent pathway. This pathway can also be activated downstream by directly activating adenylyl cyclase or PKA.
Molecules that activate cAMP pathway include:
*
cholera toxin - increases cAMP levels
*
forskolin - a
diterpene
Diterpenes are a class of terpenes composed of four isoprene units, often with the molecular formula C20H32. They are biosynthesized by plants, animals and fungi via the HMG-CoA reductase pathway, with geranylgeranyl pyrophosphate being a primary ...
natural product that activates adenylyl cyclase
*
caffeine
Caffeine is a central nervous system (CNS) stimulant of the methylxanthine chemical classification, class and is the most commonly consumed Psychoactive drug, psychoactive substance globally. It is mainly used for its eugeroic (wakefulness pr ...
and
theophylline
Theophylline, also known as 1,3-dimethylxanthine, is a drug that inhibits phosphodiesterase and blocks adenosine receptors. It is used to treat chronic obstructive pulmonary disease (COPD) and asthma. Its pharmacology is similar to other met ...
inhibit cAMP phosphodiesterase, which degrades cAMP - thus enabling higher levels of cAMP than would otherwise be had.
*
bucladesine (dibutyryl cAMP, db cAMP) - also a phosphodiesterase inhibitor
*
pertussis toxin, which increases cAMP levels by inhibiting Gi to its GDP (inactive) form. This leads to an increase in adenylyl cyclase activity, thereby increasing cAMP levels, which can lead to an increase in insulin and therefore hypoglycemia
Deactivation
The G
s alpha subunit slowly catalyzes the hydrolysis of GTP to GDP, which in turn deactivates the G
s protein, shutting off the cAMP pathway. The pathway may also be deactivated downstream by directly inhibiting adenylyl cyclase or dephosphorylating the proteins phosphorylated by PKA.
Molecules that inhibit the cAMP pathway include:
* cAMP
phosphodiesterase converts cAMP into AMP by breaking the phosphodiester bond, in turn reducing the cAMP levels
*
Gi protein, which is a G protein that inhibits adenylyl cyclase, reducing cAMP levels.
References
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EC 4.6.1
Cell signaling
Signal transduction
Cell biology
Neurochemistry