Cyclic Amp in Genome action
Cyclic AMP or Cyclic Adenosine Monophosphate is the second messenger
important in many biological actions at the cellular level. It is the chemical
messenger is generated in the cell membrane from Adenosine triphosphate or
ATP in response to a signal from the first messenger (Hormone). cAMP is used for
intracellular signal transduction in many organisms conveying the cAMP
dependent pathway.
cAMP is synthesized from ATP by adenyl cyclase located on the inner side of the
plasma membrane. Adenyl cyclase is activated by a range of signaling molecules
through the activation of adenyl cyclase stimulatory G (Gs)-protein-coupled
receptors present on the cell membrane. The production of cAMP is inhibited by
agonists of adenyl cyclase inhibitory G (Gi)-protein-coupled receptors .cAMP
decomposition into AMP is catalyzed by the enzyme phosphodiesterase.
cAMP-dependent protein kinase
Many biochemical processes such as regulation of glycogen, glucose, lipid
metabolisms are under the control of the cAMP and its associated protein
kinases. cAMP works by activating protein kinase A known as cAMP dependent
Protein Kinase.PKA is normally exists as an inactive tetrameric holoenzyme, that
consists of two catalytic and two regulatory units called C2 and R2, 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. 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 hormone causes a release
of growth hormone.
Protein kinase A
Protein kinase A is a group of enzymes whose activity is dependent on the level
of cyclic AMP in the cell.PKA is also known as cAMP-dependent protein kinase.
Protein kinase A has several functions in the cell, including regulation
of glycogen, sugar, and lipid metabolism. It is important in regulating cell cycle,
along with the protein Cyclin.
Each PKA is a holoenzyme that consists of two regulatory and
two catalytic subunits. Under low levels of cAMP, the holoenzyme remains intact
and is catalytically inactive. When the concentration of cAMP rises (e.g.,
activation of adenylate cyclases by G protein-coupled receptors coupled to Gs,
inhibition of phosphodiesterases that degrade cAMP), cAMP binds to the
two binding sites on the regulatory subunits, which leads to the release of the
catalytic subunits. The 2 regulatory subunits of protein kinase A are important for
localizing the kinase inside the cell. With the aid of A-kinase anchor
protein (AKAP), AKAP binds both to the regulatory subunits and to either a
component of cytoskeleton structure or a membrane of an organelle, anchoring
the enzyme complex to a particular sub cellular compartment.
The mechanisms PKA action may be divided into direct protein phosphorylation
and protein synthesis:
In direct protein phosphorylation PKA directly either increases or decreases the
activity of a protein. In protein synthesis PKA first directly activates CREB, which
binds the cAMP response element, altering the transcription and therefore the
synthesis of the protein. This mechanism generally takes longer time.
PKA phosphorylates other proteins, altering their function. However, which
proteins are available for phosphorylation will first depend upon what kind of cell
the PKA activity is present within, since protein composition varies from cell type
to cell type. Thus, the effects of PKA activity varies with cell type:
Genomic Action of Cyclic Amp
Many actions of second messengers initiate immediate cellular responses such as
opening or closing of ion gates, stimulation of cellular secretion, and stimulation
of muscle contraction or relaxation. Some of the actions are slower in
commencement but more are fast. In some cells, the action of cAMP is mediated
at the genomic level. Since the actions of some hormones that elevates
intracellular cAMP levels are blocked by the actions of Actino- myosin D and
Cyclohexamide, inhibitors of transcription and translation respectively.
Cyclic AMP mediates its action by way of PKA, which can phosphorylate a number
of proteins depending on the particular cell types. One such protein common to
the genomic actions of the cAMP is the cAMP responsive element (CRE) binding
protein CREB. This transcription factor is phosphorylated by Camp-activated PKA.
Phosphorylation of CREB by PKA allows the transcription factor to interact with
the CRE (a DNA sequence) to activate transcription of a cell specific mRNA for
protein synthesis. Some genes do not have the CRE consensus sequence, yet their
expression is regulated by the level of cAMP. For example, PKA also
phosphorylates some structural proteins associated with chromatin to modify
their interactions with the DNA.
Prepared by R.S.Revathy
Final year M.Sc Zoology
Govt.College for Women
Trivandrum, Kerala, India