Second messenger system


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Second messenger system

  2. 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. 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
  5. 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 Protein Kinase A (PKA) — a cAMP-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. 6. 1. The ligand binds to the receptor, altering its conformation and increasing its affinity for the G protein to which it binds. 2. The G subunit releases its GDP, which is replaced by GTP. 3. 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. 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. 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. 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 Protein Kinase G (PKG)  cGMP serves as the second messenger for  nitric oxide (NO)  the response of the rods of the retina to light.
  10. 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 (PIP2)  Phosphatidylinositol-3,4,5-trisphosphate (PIP3)  Intracellular enzyme phospholipase C (PLC),hydrolyzes PIP2 which is found in the inner layer of the plasma membrane. Hydrolysis of PIP2 yields two products:  Diacylglycerol (DAG)  Inositol-1,4,5-trisphosphate (IP3) PHOSPHO INOSITIDES.
  11. 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. 12. INOSITOL TRIPHOSPHATE, IP3  This soluble molecule diffuses through the cytosol and binds to receptors on the endoplasmic reticulum causing the release of calcium ions (Ca2+) 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. 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 PIP2 to yield two products – DAG and IP3.  Both of these products act as second messengers.  So, the cleavage of PIP2 by PLC is the functional equivalent of the synthesis of cAMP by adenylyl cyclase.
  14. 14. FORMATION OF DAG & IP3
  15. 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. 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. 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. 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. 19. REFERENCES  Karp, Gerald. Cell and Molecular biology, 6th edition, John Wiley and Sons, Inc.  Rastogi S.C, Cell and Molecular biology, 3rd edition (2010), New Age International (P) Limited, publishers.  Twyman R.M, Advanced Molecular Biology (2003), Viva Books Private Limited, New Delhi.  S/Second_messengers.html 