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
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- PKA_ 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.
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Final year M.Sc Zoology
Govt.College for Women
Trivandrum, Kerala, India