Cyclic amp

Cyclic adenosine monophosphate

1. CYCLIC AMP Bhagya Siripalli , Dept . of pharmacology, SVIPS.

2. INTRODUCTION Cyclic adenosine monophosphate  ( cAMP ,  cyclic AMP , or  3',5'-cyclic adenosine monophosphate ) is a second messenger  important in many biological processes. cAMP is a derivative of  adenosine triphosphate  (ATP) and used for intracellular signal transduction in many different organisms, conveying the cAMP-dependent pathway. It should not be confused with  5'- AMP-activated protein kinase (AMP-activated protein kinase).

3. INTRODUCTION The extracellular molecules ( hormones) that bind to a receptor is the 1 st messenger of a pathway. Hormones forms HR complex and eventually leads to formation of second messengers. Second messengers are intracellular non-protein, water soluble signal molecules that spread throughout a cell by diffusion. They relay signals for receptors on cell surface to target molecules inside cells. It significantly amplifies the strength of signals. One of major second messenger is cyclic AMP (CYCLIC ADENOSINE MONOPHOSPHATE ) Earl Wilbur Sutherland Jr., discovered second messenger for which he won 1971 Nobel prize .

4. Hormones that use the adenylyl cyclase- AMP Pathway ACTH Angiotensin-2 (epithelial cells) Calcitonin Catecholamines CRH FSH Glucagon HCG LH PTH Secretin Somatostatin TSH Vasopressin

5. STEPS INVOLVED….. Step1 : BINDING OF HORMONE to a specific receptor in the cell membrane Step2 : ACTIVATION OF G-PROTEIN after the formation of HR complex, GDP is replaced by GTP. Step3 : ACTIVATION OF ENZYME ADENYLATE CYCLASE activated G-protein either stimulates or inhibits the enzyme adenylate cyclase which is located in plasma membrane Step4 : FORMATION OF cAMP the part of enzyme adenylyl cyclase protrudes through the inner surface of the cell membrane and when activated it catalyse the formation of cAMP from cytoplasmic ATP with Mg2+ as cofactor. Thus a stimulatory G-protein increases the cAMP level whereas inhibitory G protein decreases the cAMP level. Step5 : Action of cAMP : it activates protein kinase A. One molecule of cAMP stimulates many enzyme, therefore even a slightest amount of hormone acting on cell surface can initiate a powerful response.

6. TERMINATION OF CYCLIC-AMP ACTIONS The actions of cAMP in the cell are terminated In two ways: cAMP is degraded to 5’ -AMP in the cell by the cytoplasmic enzyme Phosphodiesterase (PDE) Serine or threonine specific phosphatases dephosphorylates the protein already phosphorylated by PKA.

7. ADENYLYL CYCLASE (activated) E CF R PLASMA MEMBRANE G PROTEIN H A TP c A M P Mg2 + Activates the protein kinase A Phosphorylation P h y si o l o gi c al response 5’AMP(Inactive) P DE ICF

8. cAMP is a second messenger, used for intracellular signal transduction, such as transferring into cells the effects of hormones like glucagon and adrenaline, which cannot pass through the plasma membrane. It is also involved in the activation of protein kinases . In addition, cAMP binds to and regulates the function of ion channels such as the HCN channels and a few other cyclic nucleotide-binding proteins such as Epac1 and RAPGEF2. FUN CTIONS

9. Role in eukaryotic cells In cell biology,  protein kinase A  ( PKA [N 1] ) is a family of enzymes whose activity is dependent on cellular levels of cyclic AMP (cAMP). 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. Role in bacteria In bacteria, 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,  adenylate 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 enzymes that can supply energy independent of glucose.

10. Since cyclic AMP is a second messenger and plays vital role in cell signaling, it has been implicated in various disorders but not restricted to the roles given below: Role 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 in prefrontal cortex disorders Recent research suggests that cAMP affects the function of higher-order thinking in the prefrontal cortex through its regulation of ion channels called hyper polarization-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. P athology

11. CLINICAL IMPORTANCE Not only, many hormones act through Camp but also, toxins released by various pathogens by altering cAMP concentration in the cell STIMULATION OF cAMP : as in the case of cholera INHIBITION OF cAMP : as in case of pertussis, A component of pertussis toxin decreases adenylyl Cyclase activity by inhibitory G protein. This impairs the host’s defense ability

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