Second messenger system

1. BY, DAMARIS BENNY DANIEL I Msc . ZOOLOGY SECOND MESSENGER SYSTEM

2. INTRODUCTION Second messengers  are molecules that relay signals from receptors on the cell surface to target molecules inside the cell. They greatly amplify the strength of the signal, cause some kind of change in the activity of the cell. They are a component of cell signaling pathways. Earl Wilbur Sutherland Jr ., discovered second messengers, for which he won the 1971 Nobel Prize.

3. second messengers Short lived intracellular signaling molecules Elevated concentration of second messenger leads to rapid alteration in the activity of one or more cellular enzymes Removal or degradation of second messenger terminate the cellular response Four classes of second messengers Cyclic nucleotides Membrane lipid derivatives Ca2+ Nitric oxide/carbon monoxide

4. TYPES OF SECOND MESSENGERS

5. CYCLIC AMP cAMP is a second messenger that is synthesized from ATP by the action of the enzyme adenylyl cyclase . Binding of the hormone to its receptor activates a G protein which, in turn, activates adenylyl cyclase . Leads to appropriate response in the cell by either (or both): using P rotein K inase A ( PKA ) — a c A MP -dependent protein kinase that phosphorylates target proteins;  cAMP  binds to a protein called CREB ( cAMP  response element binding protein ), and the resultant complex controls transcription of genes. Eg.of cAMP action - adrenaline, glucagon, LH

6. The ligand binds to the receptor , altering its conformation and increasing its affinity for the G protein to which it binds. The G subunit releases its GDP, which is replaced by GTP . The α subunit dissociates from the G complex and binds to an effector (in this case adenylyl cyclase ), activating the effector . 4. Activated adenylyl cyclase produces cAMP . . The mechanism of receptor-mediated activation and inhibition of cAMP

7. 5. The GTPase activity of G hydrolyzes the bound GTP, deactivating G. 6. G reassociates with G, reforming the trimeric G protein, and the effector ceases its activity. 7. The receptor has been phosphorylated by a GRK 8. The phosphorylated receptor has been bound by an arrestin molecule, which inhibits the ligand -bound receptor from activating additional G proteins.

8. Glucose Mobilization: An Example of a Response Induced by cAMP Binding of hormone Activation of enzyme and formation of cAMP . cAMP binds to PKA & activates it. PKA phosphorylates 2 enzymes: phosphorylates glycogen phosphorylase - stimulates glycogen breakdown. inhibition – prevents conversion of glucose to glycogen. 1. Phosphorylase kinase – 2.Glycogen synthetase –

9. CYCLIC GMP cGMP is synthesized from the nucleotide GTP using the enzyme guanylyl cyclase . Nitric oxide  stimulates the synthesis of  cGMP  . Many cells contain a  cGMP - stimulated protein kinase that contains both catalytic and regulatory subunits. Some of the effects of cGMP are mediated through P rotein K inase G ( PKG ) cGMP serves as the second messenger for nitric oxide (NO) the response of the rods of the retina to light.

10. PHOSPHATIDYLINOSITOL-DERIVED SECOND MESSENGERS Phosphatidylinositol ( PI) is a negatively charged phospholipid and a minor component in eukaryotic cell membranes. The inositol can be phosphorylated to form Phosphatidylinositol-4-phosphate (PIP) Phosphatidylinositol-4,5-bis-phosphate (PIP 2 )  Phosphatidylinositol-3,4,5-trisphosphate (PIP 3 )  Intracellular enzyme phospholipase C ( PLC ), hydrolyzes PIP 2 which is found in the inner layer of the plasma membrane. Hydrolysis of PIP 2 yields two products: Diacylglycerol (DAG) Inositol-1,4,5-trisphosphate (IP 3 ) PHOSPHO INOSITIDES .

11. DIACYLGLYCEROL Diacylglycerol stimulates protein kinase C activity by greatly increasing the affinity of the enzyme for calcium ions. Protein kinase C phosphorylates specific serine and threonine residues in target proteins. Known target proteins include  calmodulin , the glucose transporter, HMG- CoA reductase ,  cytochrome P450 etc.

12. INOSITOL TRIPHOSPHATE, IP 3 This soluble molecule diffuses through the cytosol and binds to receptors on the endoplasmic reticulum causing the release of calcium ions (Ca 2+ ) into the cytosol . The rise in intracellular calcium triggers the response. Example: the calcium rise is needed for NF-AT (the "nuclear factor of activated T cells") to turn on the appropriate genes in the nucleus.

13. MODE OF ACTION Peptide and protein hormones like vasopressin, TSH, and neurotransmitters like GABA bind to GPCRs This activate the intracellular enzyme phospholipase C (PLC).   PLC in turn cleaves  PIP 2  to yield two products – DAG and IP 3 . Both of these products act as second messengers. So, the cleavage of PIP 2  by PLC is the functional equivalent of the synthesis of  cAMP  by adenylyl cyclase .

14. FORMATION OF DAG & IP3

15. CALCIUM IONS Many cells respond to extracellular stimuli by altering their intracellular calcium concentration. Ca++ acts as a second messenger in two ways: it binds to an effector molecule , such as an enzyme, activating it; it binds to an intermediary cytosolic calcium binding protein such as calmodulin . The binding of Ca++ causes profound conformational changes in calmodulin that increase calmodulin`s affinity for its effector molecules. Calmodulin , when activated, causes contraction of smooth muscles.

16. NITRIC OXIDE Nitric oxide (NO) acts as a second messenger because it is a free radical that can diffuse through the plasma membrane and affect nearby cells. It is synthesised from arginine and oxygen by the NO synthase . It activates soluble guanylyl cyclase , which when activated produces another second messenger, cGMP . It is toxic in high concentrations , but is the cause of many other functions like relaxation of blood vessels, apoptosis etc.

17. RECENT DEVELOPMENTS Feng -Yen Li, a student of PhD in biomedical sciences at UCSF, discovered a "second-messenger" role for magnesium in T cell signalling , by studying a family of two boys who suffer from chronic Epstein-Barr virus infections. A new Second Messenger, c- di -AMP was discovered  in  Staphylococcus aureus with a Role in Controlling Cell Size and Envelope Stress. This work was published in the September 2011 Issue of  PLoS Pathogens.

18. CONCLUSION Signal transduction pathways allow cells to respond to environmental signals. In these pathways, a signal is amplified. This signal amplification is brought about by second messengers like c AMP, ,c GMP, Ca ions, IP3, DAG and NO. Second messengers essentially serve as chemical relays from the plasma membrane to the cytoplasm, thus carrying out intracellular signal transduction .

19. REFERENCES Karp, Gerald . Cell and Molecular biology , 6 th edition, John Wiley and Sons, Inc. Rastogi S.C , Cell and Molecular biology , 3 rd edition (2010), New Age International (P) Limited, publishers. Twyman R.M , Advanced Molecular Biology (2003), Viva Books Private Limited, New Delhi. http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/S/Second_messengers.html http://en.wikipedia.org/wiki/Second_messenger_system