Cyclic adenosine monophosphate
Encyclopedia
Cyclic adenosine monophosphate (cAMP, cyclic AMP or 3'-5'-cyclic adenosine monophosphate
) is a second messenger important 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.
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 (such as cyclic adenosine monophosphate, cyclic AMP).
)-protein-coupled receptors and inhibited by agonists of adenylyl cyclase inhibitory G (Gi)-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
.
s like glucagon
and adrenaline, which cannot pass through the cell membrane. It is involved in the activation of protein kinase
s and regulates the effects of adrenaline and glucagon. It also regulates the passage of Ca2+
through ion channels.
, sugar
, and lipid
metabolism
.
In humans, cyclic AMP works by activating protein kinase A (PKA, cAMP-dependent protein kinase
). PKA is normally inactive as a tetrameric holoenzyme, consisting of two catalytic
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 activating the catalytic units and enabling them 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 channel
s, 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 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
.
, 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, adenylyl 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 enzyme
s 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.
, the chemotactic
movement of cells is organized by periodic waves of cAMP that propagate through the cell. 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.
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 the prefrontal cortex
. This research, especially the cognitive deficits in age-related illnesses and ADHD, is of interest to researchers studying the brain.
Adenosine monophosphate
Adenosine monophosphate , also known as 5'-adenylic acid, is a nucleotide that is used as a monomer in RNA. It is an ester of phosphoric acid and the nucleoside adenosine. AMP consists of a phosphate group, the sugar ribose, and the nucleobase adenine...
) is a second messenger important in many biological processes. cAMP is derived from adenosine triphosphate
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...
(ATP) and used for intracellular signal transduction
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...
in many different organisms, conveying the cAMP-dependent pathway.
History
Earl Sutherland of Vanderbilt UniversityVanderbilt University
Vanderbilt University is a private research university located in Nashville, Tennessee, United States. Founded in 1873, the university is named for shipping and rail magnate "Commodore" Cornelius Vanderbilt, who provided Vanderbilt its initial $1 million endowment despite having never been to the...
won a Nobel Prize in Physiology or Medicine
Nobel Prize in Physiology or Medicine
The Nobel Prize in Physiology or Medicine administered by the Nobel Foundation, is awarded once a year for outstanding discoveries in the field of life science and medicine. It is one of five Nobel Prizes established in 1895 by Swedish chemist Alfred Nobel, the inventor of dynamite, in his will...
in 1971 "for his discoveries concerning the mechanisms of the action of hormones," especially epinephrine, via second messengers (such as cyclic adenosine monophosphate, cyclic AMP).
Synthesis and decomposition
cAMP is synthesised from ATP by adenylyl cyclase located on the inner side of the plasma membrane. Adenylyl cyclase is activated by a range of signaling molecules through the activation of adenylyl cyclase stimulatory G (GsGs 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:...
)-protein-coupled receptors and inhibited by agonists of adenylyl cyclase inhibitory G (Gi)-protein-coupled receptors. Liver adenylyl cyclase responds more strongly to glucagon, and muscle adenylyl cyclase responds more strongly to adrenaline.
cAMP decomposition into AMP
Adenosine monophosphate
Adenosine monophosphate , also known as 5'-adenylic acid, is a nucleotide that is used as a monomer in RNA. It is an ester of phosphoric acid and the nucleoside adenosine. AMP consists of a phosphate group, the sugar ribose, and the nucleobase adenine...
is catalyzed by the enzyme 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...
.
Functions
cAMP is a second messenger, used for intracellular signal transduction, such as transferring the effects of hormoneHormone
A hormone is a chemical released by a cell or a gland in one part of the body that sends out messages that affect cells in other parts of the organism. Only a small amount of hormone is required to alter cell metabolism. In essence, it is a chemical messenger that transports a signal from one...
s like glucagon
Glucagon
Glucagon, a hormone secreted by the pancreas, raises blood glucose levels. Its effect is opposite that of insulin, which lowers blood glucose levels. The pancreas releases glucagon when blood sugar levels fall too low. Glucagon causes the liver to convert stored glycogen into glucose, which is...
and adrenaline, which cannot pass through the cell membrane. It is involved in the activation of protein kinase
Protein kinase
A protein kinase is a kinase enzyme that modifies other proteins by chemically adding phosphate groups to them . Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins...
s and regulates the effects of adrenaline and glucagon. It also regulates the passage of Ca2+
Calcium
Calcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth-most-abundant element by mass in the Earth's crust...
through ion channels.
In humans
cAMP and its associated kinases function in several biochemical processes, including the regulation of glycogenGlycogen
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...
, sugar
Sugar
Sugar is a class of edible crystalline carbohydrates, mainly sucrose, lactose, and fructose, characterized by a sweet flavor.Sucrose in its refined form primarily comes from sugar cane and sugar beet...
, and lipid
Lipid
Lipids constitute a broad group of naturally occurring molecules that include fats, waxes, sterols, fat-soluble vitamins , monoglycerides, diglycerides, triglycerides, phospholipids, and others...
metabolism
Metabolism
Metabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...
.
In humans, cyclic AMP 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...
). PKA is normally inactive as a tetrameric holoenzyme, consisting of two catalytic
Catalysis
Catalysis is the change in rate of a chemical reaction due to the participation of a substance called a catalyst. Unlike other reagents that participate in the chemical reaction, a catalyst is not consumed by the reaction itself. A catalyst may participate in multiple chemical transformations....
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 activating the catalytic units and enabling them 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 channel
Calcium channel
A Calcium channel is an ion channel which displays selective permeability to calcium ions. It is sometimes synonymous as voltage-dependent calcium channel, although there are also ligand-gated calcium channels.-Comparison tables:...
s, providing a minor pathway by which growth hormone-releasing hormone causes a release of growth hormone
Growth hormone
Growth hormone is a peptide hormone that stimulates growth, cell reproduction and regeneration in humans and other animals. Growth hormone is a 191-amino acid, single-chain polypeptide that is synthesized, stored, and secreted by the somatotroph cells within the lateral wings of the anterior...
.
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 exchange factor (GEF) activity was discovered. These are termed Exchange proteins activated by cAMP (Epac) and the family comprises Epac1
RAPGEF3
Rap guanine nucleotide exchange factor 3 is a protein that in humans is encoded by the RAPGEF3 gene.-Further reading:...
and Epac2
RAPGEF4
Rap guanine nucleotide exchange factor 4 , also known as exchange protein directly activated by cAMP 2 , is a protein which in humans is encoded by the RAPGEF4 gene.-Further reading:...
. 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
Rap1
Rap1 is a small GTPase, which are small cytosolic proteins that act like cellular switches and are vital for effective signal transduction. There are two isoforms of the Rap1 protein, each encoded by a separate gene, RAP1A and RAP1B...
.
Role of cAMP in bacteria
In bacteriaBacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...
, 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, adenylyl cyclase, as a side-effect of glucose transport into the cell. The transcription factor cAMP receptor protein
CAMP receptor protein
cAMP receptor protein is a regulatory protein in bacteria. This protein binds cAMP, which causes a conformational change that allows the protein to bind tightly to a specific DNA sequence in the promoters of the genes it controls...
(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 enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
s that can supply energy independent of glucose.
cAMP, for example, is involved in the positive regulation of the lac operon
Lac operon
The lac operon is an operon required for the transport and metabolism of lactose in Escherichia coli and some other enteric bacteria. It consists of three adjacent structural genes, lacZ, lacY and lacA. The lac operon is regulated by several factors including the availability of glucose and of...
. In an environment of a low glucose concentration, cAMP accumulates and binds to the allosteric site on CRP (cAMP receptor protein
CAMP receptor protein
cAMP receptor protein is a regulatory protein in bacteria. This protein binds cAMP, which causes a conformational change that allows the protein to bind tightly to a specific DNA sequence in the promoters of the genes it controls...
), 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 some slime moulds
In the species Dictyostelium discoideumDictyostelid
The dictyostelids are a group of cellular slime molds, or social amoebae.-Slug behavior:When food is readily available they are individual amoebae, which feed and divide normally...
, the chemotactic
Chemotaxis
Chemotaxis is the phenomenon in which somatic cells, bacteria, and other single-cell or multicellular organisms direct their movements according to certain chemicals in their environment. This is important for bacteria to find food by swimming towards the highest concentration of food molecules,...
movement of cells is organized by periodic waves of cAMP that propagate through the cell. 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 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 cortexPrefrontal cortex
The prefrontal cortex is the anterior part of the frontal lobes of the brain, lying in front of the motor and premotor areas.This brain region has been implicated in planning complex cognitive behaviors, personality expression, decision making and moderating correct social behavior...
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 the prefrontal cortex
Prefrontal cortex
The prefrontal cortex is the anterior part of the frontal lobes of the brain, lying in front of the motor and premotor areas.This brain region has been implicated in planning complex cognitive behaviors, personality expression, decision making and moderating correct social behavior...
. This research, especially the cognitive deficits in age-related illnesses and ADHD, is of interest to researchers studying the brain.
See also
- Cyclic guanosine monophosphateCyclic guanosine monophosphateCyclic guanosine monophosphate is a cyclic nucleotide derived from guanosine triphosphate . cGMP acts as a second messenger much like cyclic AMP...
(cGMP) - 8-Bromoadenosine 3',5'-cyclic monophosphate8-Bromoadenosine 3',5'-cyclic monophosphate8-Bromoadenosine 3',5'-cyclic monophosphate is a brominated derivative of cyclic adenosine monophosphate . 8-Br-cAMP is an activator of cyclic AMP-dependent protein kinase, and it is long-acting because it is resistant to degradation by cyclic AMP phosphodiesterase....
(8-Br-cAMP) - AcrasinAcrasinEach species of slime mold has its own specific chemical messenger, collectively referred to as acrasins. These chemicals signal that lots of individual cells should move towards each other to form a single large cell or plasmodium...
specific to chemotactic use in Dictyostelium discoideum. - phosphodiesterase 4 (PDE 4) which degrades cAMP