CAMP dependent pathway
Encyclopedia
In the field of molecular biology
Molecular biology
Molecular biology is the branch of biology that deals with the molecular basis of biological activity. This field overlaps with other areas of biology and chemistry, particularly genetics and biochemistry...

, the cAMP-dependent pathway, also known as the adenylyl cyclase
Adenylate cyclase
Adenylate cyclase is part of the G protein signalling cascade, which transmits chemical signals from outside the cell across the membrane to the inside of the cell ....

 pathway
, is a G protein-coupled receptor
G protein-coupled receptor
G protein-coupled receptors , also known as seven-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptor, and G protein-linked receptors , comprise a large protein family of transmembrane receptors that sense molecules outside the cell and activate inside signal...

-triggered signaling cascade
Signal transduction
Signal transduction occurs when an extracellular signaling molecule activates a cell surface receptor. In turn, this receptor alters intracellular molecules creating a response...

 used in cell communication.

Mechanism

G protein-coupled receptors (GPCRs) are a large family of integral membrane protein
Integral membrane protein
An integral membrane protein is a protein molecule that is permanently attached to the biological membrane. Proteins that cross the membrane are surrounded by "annular" lipids, which are defined as lipids that are in direct contact with a membrane protein...

s that respond to a variety of extracellular stimuli. Each GPCR binds to and is activated by a specific ligand
Ligand
In coordination chemistry, a ligand is an ion or molecule that binds to a central metal atom to form a coordination complex. The bonding between metal and ligand generally involves formal donation of one or more of the ligand's electron pairs. The nature of metal-ligand bonding can range from...

 stimulus that ranges in size from small molecule catecholamine
Catecholamine
Catecholamines are molecules that have a catechol nucleus consisting of benzene with two hydroxyl side groups and a side-chain amine. They include dopamine, as well as the "fight-or-flight" hormones adrenaline and noradrenaline released by the adrenal medulla of the adrenal glands in response to...

s, lipids, or neurotransmitter
Neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...

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
Heterotrimeric G protein
"G protein" usually refers to the membrane-associated heterotrimeric G proteins, sometimes referred to as the "large" G proteins. These proteins are activated by G protein-coupled receptors and are made up of alpha , beta and gamma subunits, the latter two referred to as the beta-gamma...

 complex. The Gs alpha subunit
Gs alpha subunit
The Gs alpha subunit is a heterotrimeric G protein subunit that activates the cAMP-dependent pathway by activating adenylate cyclase.-Receptors:The G protein-coupled receptors that couple to this kind of G-protein include:...

 of the stimulated G protein complex exchanges GDP
Guanosine diphosphate
Guanosine diphosphate, abbreviated GDP, is a nucleoside diphosphate. It is an ester of pyrophosphoric acid with the nucleoside guanosine. GDP consists of the pyrophosphate group, the pentose sugar ribose, and the nucleobase guanine....

 for GTP
Guanosine triphosphate
Guanosine-5'-triphosphate is a purine nucleoside triphosphate. It can act as a substrate for the synthesis of RNA during the transcription process...

 and is released from the complex.

In a cAMP-dependent pathway, the activated Gs alpha subunit binds to and activates an enzyme called adenylyl cyclase, which, in turn, catalyzes the conversion of ATP
Adenosine triphosphate
Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...

 into cyclic adenosine monophosphate
Cyclic adenosine monophosphate
Cyclic adenosine monophosphate is a second messenger important in many biological processes...

 (cAMP).
Increases in concentration of the second messenger cAMP may lead to the activation of
  • cyclic nucleotide-gated ion channel
    Cyclic nucleotide-gated ion channel
    Cyclic nucleotide-gated ion channels are ion channels that function in response to the binding of cyclic nucleotides. CNG channels are nonselective cation channels that are found in the membranes of various types of cells.- Discovery :...

    s
  • exchange proteins activated by cAMP (EPAC) such as RAPGEF3
    RAPGEF3
    Rap guanine nucleotide exchange factor 3 is a protein that in humans is encoded by the RAPGEF3 gene.-Further reading:...

  • an enzyme called protein kinase A (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
    Glycogen is a molecule that serves as the secondary long-term energy storage in animal and fungal cells, with the primary energy stores being held in adipose tissue...

     into glucose
    Glucose
    Glucose is a simple sugar and an important carbohydrate in biology. Cells use it as the primary source of energy and a metabolic intermediate...

  • enzymes that promote muscle contraction in the heart leading to an increase in heart rate
  • transcription factor
    Transcription factor
    In molecular biology and genetics, a transcription factor is a protein that binds to specific DNA sequences, thereby controlling the flow of genetic information from DNA to mRNA...

    s, which regulate gene expression


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
CAMP-dependent protein kinase
In cell biology, Protein kinase A refers to a family of enzymes whose activity is dependent on cellular levels of cyclic AMP . PKA is also known as cAMP-dependent protein kinase...

), and, thus, 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.

This pathway can activate enzyme
Enzyme activator
Enzyme activators are molecules that bind to enzymes and increase their activity, and are often called coenzymes or cofactors. These molecules are often involved in the allosteric regulation of enzymes in the control of metabolism...

s and regulate gene expression
Gene expression
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product. These products are often proteins, but in non-protein coding genes such as ribosomal RNA , transfer RNA or small nuclear RNA genes, the product is a functional RNA...

. 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
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...

.

Activation

Activated GPCRs cause a conformational change in the attached G protein complex, which results in the Gs alpha subunit's exchanging GDP for GTP and separation from the beta and gamma subunits. The Gs 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
    Cholera toxin
    Cholera toxin is a protein complex secreted by the bacterium Vibrio cholerae. CTX is responsible for the massive, watery diarrhea characteristic of cholera infection.- Structure :...

     - increase cAMP levels
  • forskolin
    Forskolin
    Forskolin is a labdane diterpene that is produced by the Indian Coleus plant . Forskolin is commonly used to raise levels of cyclic AMP in the study and research of cell physiology. Forskolin resensitizes cell receptors by activating the enzyme adenylyl cyclase and increasing the intracellular...

     - a diterpene
    Terpene
    Terpenes are a large and diverse class of organic compounds, produced by a variety of plants, particularly conifers, though also by some insects such as termites or swallowtail butterflies, which emit terpenes from their osmeterium. They are often strong smelling and thus may have had a protective...

     natural product that activates adenylyl cyclase
  • caffeine
    Caffeine
    Caffeine is a bitter, white crystalline xanthine alkaloid that acts as a stimulant drug. Caffeine is found in varying quantities in the seeds, leaves, and fruit of some plants, where it acts as a natural pesticide that paralyzes and kills certain insects feeding on the plants...

     and theophylline
    Theophylline
    Theophylline, also known as dimethylxanthine, is a methylxanthine drug used in therapy for respiratory diseases such as COPD and asthma under a variety of brand names. Because of its numerous side-effects, the drug is now rarely administered for clinical use. As a member of the xanthine family, it...

     inhibit cAMP phosphodiesterase, which leads to an activation of G proteins that result in the activation of the cAMP pathway
  • bucladesine
    Bucladesine
    Bucladesine is a cyclic nucleotide derivative which mimics the action of endogenous cAMP and is a phosphodiesterase inhibitor.Bucladesine is a cell permeable cAMP analog. The compound is used in a wide variety of research applications because it mimics cAMP and can induce normal physiological...

     (dibutyryl cAMP, db cAMP) - also a phosphodiesterase inhibitor
  • pertussis toxin
    Pertussis toxin
    Pertussis toxin is a protein-based AB5-type exotoxin produced by the bacterium Bordetella pertussis, which causes whooping cough. PT is involved in the colonization of the respiratory tract and the establishment of infection...

    , which increase cAMP levels by inhibiting Gi to its GDP (inactive) form. This leads to an increase in adenylyl cyclase, therefore increasing cAMP levels, which can lead to an increase in insulin and therefore hypoglycemia

Deactivation

The Gs alpha subunit slowly catalyzes the hydrolysis of GTP to GDP, which in turn deactivates the Gs 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
    Phosphodiesterase
    A phosphodiesterase is any enzyme that breaks a phosphodiester bond. Usually, people speaking of phosphodiesterase are referring to cyclic nucleotide phosphodiesterases, which have great clinical significance and are described below...

     dephospohorylates cAMP into AMP, reducing the cAMP levels
  • Gi protein, which is a G protein that inhibits adenylyl cyclase, reducing cAMP levels.
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