Slideshare second messengers aj


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Slideshare second messengers aj

  1. 1. SECOND MESSENGERS Presenter : Dr.Anu Priya J
  2. 2. SCHEME • History • Introduction • Types • cAMP Pathway • cGMP Pathway • IP3 / DAG Pathway • Calcium as a second messenger • Eicosanoids • Applied aspects
  3. 3. HISTORY • Earl Wilbur Sutherland Jr. – 1971 Nobel Prize in Physiology or Medicine • Epinephrine – liver - glycogen to glucose – cAMP
  4. 4. • Martin Rodbell & Alfred G. Gilman – 1994 Nobel Prize HISTORY
  5. 5. INTRODUCTION • Cell to cell communication • Chemical and physical messengers interact with receptors in the plasma membrane , cytoplasm or nucleus. • A series of signaling events that mediate the response to each stimulus. • Response – specific, amplified ,tightly regulated and coordinated.
  6. 6. Plasma membrane EXTRACELLULAR FLUID CYTOPLASM Reception Transduction Response Receptor Signaling molecule Activation of cellular response Relay molecules in a signal transduction pathway 321 Earl Sutherland – cell signaling- 3 processes
  7. 7. • Signaling pathways are characterized by: 1. Multiple, hierarchical steps 2. Amplification of the hormone-receptor binding event which magnifies the response 3. Activation of multiple pathways and regulation of multiple cellular functions 4. Feedback mechanisms – tight regulatory control
  8. 8. TYPES • Hydrophobic molecules -Membrane associated -Phosphatidylinositol , Diacylglycerol • Hydrophilic molecules -Cytosolic - cAMP, cGMP, inositol triphosphate,Ca2+
  9. 9. • cAMP pathway • cGMP pathway • IP3 / DAG pathway • Calcium as a second messenger • Eicosanoids Second Messengers
  10. 10. 11 Second Messengers • General characteristics – Low amounts in resting state – Regulated synthesis – Regulated destruction – Act through other proteins
  11. 11. Hormone receptor GDP G protein GTP Adenylcyclase cAMP ATP cAMP pathway
  12. 12. cAMP pathway
  13. 13. cAMP-dependent Protein Kinase A C R R C + 4 cAMP C C R R cAMP cAMP cAMP cAMP + The catalytic subunit is now free to attack a protein target. cAMP pathway
  14. 14. Active phosphorylase Kinase Inactive Phosphorylase Kinase         P P Catalytic site Calmodulin 2ATP 2ADP cAPK Kinase enzymes are the targets for the catalytic subunit of PKA These target enzymes have some unique features. Phosphorylase kinase, for example, is composed of 4 different subunits . The delta subunit is calmodulin, a calcium binding protein, that regulates the activity. The gamma subunit has the catalytic site . The enzyme is not active. To activate phosphorylase kinase, the catalytic subunit of protein kinase A transfers 2 PO4s from 2 ATPs to the alpha and beta subunits. Phosphorylation at these sites renders phosphorylase kinase active. Conversely, removing phosphate inactivates the kinase.
  15. 15. P The target kinases phosphorylate enzymes that control critical steps in a pathway. For example, phosphorylase or glycogen synthase are targets of protein kinase. For phosphorylase, the kinase enzyme is phosphorylase kinase. The sequence of events is highlighted in the figure below Adenylcyclase C C R R cAMP dependent protein kinase     Phosphorylase kinase Phosphorylase Thus hormones(external to the cell) have profound effect on glycogen degradation, glycogen synthesis, and other processes by controlling the enzyme activities by the presence or absence of phosphate groups. P cAMP pathway
  16. 16. cAMP pathway
  17. 17. • In addition to signaling in the cytoplasm, the catalytic subunit of PKA can enter the nucleus of cells and phosphorylate and activate the transcription factor cAMP response element binding (CREB) protein. • Phospho-CREB protein increases the transcription of many genes • Indirect effect of cAMP mediated by PKA cAMP pathway
  18. 18. cyclic AMP mediated response Epinephrine (α2,β1,β2) Acetylcholine(M2) Norepinephrine Glucagon Somatostatin ACTH CRH ADH FSH hCG LH MSH PTH TSH Angiotensin II Calcitonin
  19. 19. cGMP Pathway Ligand-receptor Guanyl cyclase GTP cGMP Protein kinase G Active protein kinase G Effects PDE GMP
  20. 20. 22 • smooth muscle relaxation • vision • ANP,NO cGMP Pathway
  21. 21. • cGMP Pathway in phototransduction cGMP Pathway
  22. 22. Nitric oxide (NO) NO, a simple gas, is able to diffuse across the membrane, and alters the activity of intracellular target enzymes. It’s extremely unstable, so its effects are local. Ex. It signals the dilation of blood vessels. Mechanism. Acetylcholine is released from the terminus of nerve cell in the blood vessel wall. The endothelial cells are stimulated to produce NO (from arginine), which causes an increased synthesis of cGMP, a second messenger responsible for blood vessel dilation. Ach Nerve cell endothelial cell NO cGMP Vessel dilationAchR cGMP Pathway
  23. 23. IP3 /DAG LIGAND RECEPTOR ↓ G protein ↓ Phospholipase C ↓ PIP2  IP3 + DAG ↓ Endoplasmic reticulum  opening of Ca channels ↓ Ca++ ↓ Protein kinase C  Effects
  24. 24. G protein EXTRA- CELLULAR FLUID Signaling molecule (first messenger) G protein-coupled receptor Phospholipase C DAG PIP2 IP3 (second messenger) IP3-gated calcium channel Endoplasmic reticulum (ER) CYTOSOL Ca2 GTP Figure 11.14-1
  25. 25. Figure 11.14-2 G protein EXTRA- CELLULAR FLUID Signaling molecule (first messenger) G protein-coupled receptor Phospholipase C DAG PIP2 IP3 (second messenger) IP3-gated calcium channel Endoplasmic reticulum (ER) CYTOSOL Ca2 (second messenger) Ca2 GTP
  26. 26. Figure 11.14-3 G protein EXTRA- CELLULAR FLUID Signaling molecule (first messenger) G protein-coupled receptor Phospholipase C DAG PIP2 IP3 (second messenger) IP3-gated calcium channel Endoplasmic reticulum (ER) CYTOSOL Various proteins activated Cellular responses Ca2 (second messenger) Ca2 GTP
  27. 27. IP3 /DAG
  28. 28. 30 • Inositol tri-phosphate • Hydrophilic • Agonist for internal calcium channel • [Ca++]i rises • Multiple effects through Ca++-binding proteins • Diacylglycerol • Hydrophobic • Targets PKC (a kinase) • PKC requires Ca++ and DAG IP3 /DAG
  29. 29. • Classical PKC family members (PKCα,PKCβ,PKCγ) require both Ca2+ & DAG for activation. • The novel PKCs (PKCδ,PKCε,PKCη) are independent of Ca2+ IP3 /DAG
  30. 30.  Epinephrine (α1)  Acetylcholine (M1,M3)  Angiotensin  GnRH  GHRH  Oxytocin  TRH  PDGF IP3 /DAG
  31. 31. • Calcium ions - once they enter the cytoplasm exert allosteric regulatory effects on many enzymes and proteins. • Calcium acts as a second messenger by indirect signal transduction pathways such as via G protein-coupled receptors. Calcium as a 2nd Messenger
  32. 32. • Low cytoplasmic Ca++ at rest (10–100 nM). • To maintain this low concentration, Ca2+ is actively pumped from the cytosol to the extracellular space and into the endoplasmic reticulum (ER) • Certain proteins of the cytoplasm and organelles act as buffers by binding Ca2+. • Signaling occurs when the cell is stimulated to release calcium ions (Ca2+) from intracellular stores, and/or when calcium enters the cell through plasma membrane ion channels. Calcium as a 2nd Messenger
  33. 33. • sudden increase in the cytoplasmic Ca2+ level up to 500–1,000 nM by opening channels in the endoplasmic reticulum or the plasma membrane. • Phospholipase C pathway – IP3 & DAG • Eicosanoids Calcium as a 2nd Messenger
  34. 34. • Many of Ca2+-mediated events occur when the released Ca2+ binds to and activates the regulatory protein calmodulin. • Calmodulin may activate calcium-calmodulin- dependent protein kinases, or may act directly on other effector proteins. • Besides calmodulin, there are many other Ca2+-binding proteins such as troponin C that mediate the biological effects of Ca2+. Calcium as a 2nd Messenger
  35. 35. Calcium as a 2nd Messenger
  36. 36. 38 Calmodulin Targets • Adenylate cyclase • Phosphodiesterase • Myosin light chain kinase • Calmodulin-dependent kinases • Calcineurin (a phosphatase)
  37. 37. This class of lipids act as signaling molecules that bind to cell surface molecules. They include: PROSTAGLANDINS PROSTACYCLIN TROMBOXANES LEUKOTRIENES. The eicosanoids are rapidly broken down and therefore act in autocrine or paracrine pathways. They stimulate a variety of responses in their target cells, including blood platelet aggregation, inflammation, and smooth muscle contraction. EICOSANOIDS
  39. 39. Direct pathway  Serotonin(5HT2)  Glutamate(mGLUR1)  Fibroblast growth factor β  IFN α  IFN γ Indirect pathway  Dopamine(D2)  Adenosine(A1)  Norepinephrine(α2)  Serotonin(5HT1) EICOSANOIDS
  40. 40. • Caffeine and methylxanthines inhibit cAMP phosphodiesterases • Thus prolong cellular response mediated by cAMP and PKA Applied
  41. 41. • Cholera toxin – ADP ribosylation- Gαs • Pertussis toxin – ADP ribosylation- Gαi Applied
  42. 42. • McCune-Albright syndrome - A somatic mutation that constitutively activates the Gαs in a mosaic pattern - Excess cAMP - Characteristic triad i. Variable hyperfunction of multiple endocrine glands, including precocious puberty in girls ii. Bone lesions iii. Pigmented skin lesions (café au lait spots) Applied
  43. 43. Huntington’s disease • Disturbance of CREB protein in the brain can contribute to the development and progression of Huntington’s disease. • Autopsied brains of those who had Huntington's disease have been found to have incredibly reduced amounts of CREB protein Applied
  44. 44. Applied Angina pectoris Nitroglycerine ↓ Nitric oxide ↓ cGMP ↓ Protein kinase G ↓ Relax smooth muscle in coronary arteries
  45. 45. Huntington’s disease • Mutant Htt→ IP3 receptors more sensitive to IP3 → increased release of Ca2+ from ER→increase in cytosolic and mitochondrial concentration of calcium→ Ca2+ induced degeneration of GABAergic medium spiny neurons Alzheimer's Disease • Familial – mutation of PS1,PS2,APP genes →increased IP3 mediated calcium release Applied
  46. 46. Eicosanoids are synthesized from arachidonic acid. The first enzyme involved in their synthesis (cyclooxygenase, COX) is the target of ASPIRIN. Aspirin actions: -reduces inflammation and pain (inhibition of prostaglandins) - reduces platelet aggregation and blood clotting (thromboxanes) Applications: - prevention of stroke AA COX aspirin P T Applied
  47. 47. THANK YOU
  48. 48. References • Berne & Levy - Physiology, 6th Edition • Boron & Boulpaep - Medical Physiology, 2nd Edition • William’s textbook of Endocrinology,10th edition • Internet references