Chapter 26 Secondary Messengers

  1. Four types of secondary messengers
    • Cyclic Nucleotides
    • Lipids
    • Calcium
    • Nitric Oxide
  2. Characterictistic of Cyclic nucleotides
    Thy produce and remove enzymes they synthesize/degrade. Large quantity in cytoplasm. They target kinases and channels.
  3. Two cylcic nucleotide monophospahates employed as second messengers
    • cAMP
    • cGMP
  4. Cylic nucleotides target
    Protein Kinases and cyclic nucleotide gated ion chnannels
  5. Adenylylcyclase
    enzyme which synthesizes the cyclic nucleotide cAMP from ATP. Remember HIGH levels of cAMP will saturate the regulatory subunit which will dissociate from the active site allows for ACTIVATION.
  6. Regulatory mechanisms act to regulate Adenylylcylcases
    –GTP-Gα activates

    –Ca-calmodulin or protein kinase C activate

    –GTP-Gβγ activates some, inactivates others

    –GTP-Giα, PKA inactivate
  7. 3 membrabe parent lipids which are primary source of lipid signaling molecules
    • Phosphatidylinositol
    • Phosphatidylcholine
    • Sphingomyelin
  8. 3 kinds of enzymes which produce most lipid derived second messengers Products produced by these enzymes from 3 parent lipids particpate in signaling reactions
    • Phospholipases
    • Lipid kinases
    • Lipid phosphatases
  9. Phospholipase one of the enzymes that produce lipid derived second messenger
    • Different phospholipases , cleaves ester bonds and amide bond of sphngomylein.
    • Cells have three main intracellular phospholipases -PLA2, removes C2 fatty acid yields a free fatty acid in cytoplasm..
    • -PLAC, removes cleaves phosphorylated head from phophoglyceride leaves DAG in bilayer. -Sphingomyelinase leaves Ceramide in bilayer. -Phospholipase D cleaves polar head from phosphoglyceride produces phosphatidic acid. in bilayer

    IP3 in lipid bilayer?? pg 468
  10. Lipid Kinases
    • -Add phosphates to DAG to make phosphatidic
    • acid in membrane

    • -Add phosphate groups to phosphatidylinositol to make varitey of polyphosphoiniositides
    • –Phosphatidyl 4-phosphate (PI(4)P)
    • –PI(4,5)P2
    • –PI(3,4,5)P3
    • –PI(3)P
    • -PI(3,5)P
  11. Lipid Phosphatases
    reverse of kinases removes the Phosphate from phophatidic acid will make DAG.
  12. Lipid second messenger produced from Arachidonic
    acid cleaved by phospholipase A2(PLA2)
  13. Eicosanoids oxygenated via COX-1 and COX-2 and specific enzymes yield various forms
    -Prostaglandins(Many functions, some in pain reception (NSAIDs)

    • Prostacyclin:antithrombotic, vasodilation
    • Thromboxane:thrombotic, vasoconstriction
    • Leukotrienes:contribute to inflammation in asthma
  14. Lipid derived second messengers mediate their effects by
    • escape from the cell and binding to recptors on on the surface of the cell or neighboring cells sets themselves apart from classic secondary messengers which act on inside of self (exception NO) all the eicosanoids presented here activate target cells by binding G-protein coupled, 7 helix receptors.
  15. Prostaglandin secondary messenger
    A prostaglandin is any member of a group of lipid compounds that are derived enzymatically from fatty acids and have important functions in the animal body. Every prostaglandin contains 20 carbon atoms, including a 5-carbon ring. They are mediators and have a variety of strong physiological effects, such as regulating the contraction and relaxation of smooth muscle tissue. Prostaglandins are not endocrine hormones, but autocrine or paracrine, which are locally acting messenger molecules
  16. Lipid derived second messengers for intracellular communication are produced by
    phosphatidylcholine and arachidonic acid produce
  17. prostaglandin biosynthesis
    • •Arachidonic acid is processed by prostaglandin H synthetase (cyclooxygenase) to prostaglandin H2
    • COX-1,expressed by most cells
    • Prostaglandins protect stomach lining

    • •Inflammatory stimuli induce COX-2, with the same function
    • COX-1 and -2 are isozymes

    • •NSAIDs (aspirin, ibuprofen, etc.) are COX inhibitors
    • Aspirin/ibuprofen active on COX-1 and COX-2
    • SelectiveCOX-2 inhibitors effective for pain without gastric side effects, but may have other problems (e.g. VIOXX)
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Chapter 26 Secondary Messengers
Secondary messengers