CELL SIGNALLING By:        Khuram Aziz        M.phill Biochemistry
 Overview of All lectures that you have  learned Its brief description and animations
Cells also communicate by direct     contact.1.   Cell Junctions     Signaling substances dissolved in the cell can pass  ...
COMMUNICATION BY DIRECTCONTACTWITH CELLS.
Local Chemical SignalingParacrineSecreting cell acts on nearby target cell bydischarging molecules into the extracellular ...
DISTANT CELL COMMUNICATIONHormones signal target cells at much greaterdistances.Secreted into the body fluids, they reach ...
L                       LLocal and Distant Cell Communication In Animals.                      C                      O   ...
THE THREE STAGES OF CELL SIGNALINGFor a chemical signal to elicit a specificresponse, the target cell must possess asignal...
OVERVIEW OF CELLSIGNALING.
Reception – signal (ligand) binds to aspecific cell surface protein.Transduction – binding results inconformation change o...
 Many signal molecules cannot pass freely  through the plasma membrane Receptors are located on the plasma  membrane Th...
Overview of the 3 Main Signal Transduction      Pathways:             e.g., neurotransmission                   e.g., cAMP...
A LIGAND-GATED ION-CHANNEL RECEPTOR.(important in nervous system)
Signal Transduction    Themes:       •intracellular 2nd messengers           •changes in       •Protein phosphorylation1. ...
STEROID HORMONES: ACTION  Blood                Steroid 1 Most hydrophobic                                                 ...
STEROID HORMONES: ACTION  Blood 1 Most hydrophobic   steroids are bound     vessel   to plasma protein   carriers. Only   ...
STEROID HORMONES: ACTION  Blood               Steroid 1 Most hydrophobic   steroids are bound     vessel             hormo...
STEROID HORMONES: ACTION  Blood               Steroid 1 Most hydrophobic                                                  ...
STEROID HORMONES: ACTION  Blood               Steroid 1 Most hydrophobic                                                  ...
STEROID HORMONES: ACTION  Blood               Steroid 1 Most hydrophobic                                                  ...
STEROID HORMONES: ACTION  Blood                Steroid 1 Most hydrophobic                                                 ...
Please note that due to differingoperating systems, some animationswill not appear until the presentation isviewed in Pres...
THE STRUCTURE OF A G-PROTEIN –LINKEDRECEPTOR.
RECEPTORS THAT ACTIVATE GPROTEINS                            17-24
Please note that due to differingoperating systems, some animationswill not appear until the presentation isviewed in Pres...
ANOTHER RECEPTOR – G PROTEIN CYCLE
CAMP AS ASECONDMESSENGER.
c-AMP: a second messenger
OVERVIEW- GENERAL STRUCTURE Lyase Enzyme that converts ATP to cAMP Interacts with g proteins and receptors 1064-1353 a...
GENERAL STRUCTURE CONT’D   10 mammalian isoforms       All membrane bound       60% similarity       50%-90% in cytopl...
PRIMARY STRUCTURE   The main structural features of mammalian adenylyl cyclases   M1/M2: 2 sets 6 transmembrane spans  ...
ROLE OF CYCLIC AMP Step 1: activates protein kinases Step 2: protein kinases phosphorylate substrate proteins Step 3: acti...
G-protein Mediated cAMPsynthesis               a     a          g                            b                         ATP...
ADENYLYL CYCLASE      RECEPTORGDP                 GTP
G PROTEINS THAT INTERACT WITHADENYLATE CYCLASE                                17-35
WHAT DOES IT DO?
Please note that due to differingoperating systems, some animationswill not appear until the presentation isviewed in Pres...
RECEPTORS THAT DIRECTLY ALTERTHE ACTIVITY OF INTRACELLULARMEDIATOR                                17-38
G-protein mediated signal transduction ismediated by several 2nd messengers:           Adenylate cyclase                  ...
2ND MESSENGERS: IP3 AND DAG                              PLC=                              Phospholipase C                ...
HYDROLYSIS OF PIP2One of the most widespread pathways of intracellular signaling is based on thesecond messengers derived ...
LE 11-12_1      EXTRACELLULAR Signal molecule      FLUID         (first messenger)                                    G pr...
LE 11-12_2      EXTRACELLULAR Signal molecule      FLUID         (first messenger)                                      G ...
LE 11-12_3      EXTRACELLULAR Signal molecule      FLUID         (first messenger)                                      G ...
Ca2+ pool can be affected in 2 ways:1. Ligand binding to a calcium ion channel2. Activation of IP3 signaling pathway
G PROTEINS THAT OPEN CALCIUM IONCHANNELS                                   17-46
Please note that due to differingoperating systems, some animationswill not appear until the presentation isviewed in Pres...
ligand -gated(IP3)                                       ligand -gated                                       (Ca2+ )      ...
HYDROLYSIS OF PIP2One of the most widespread pathways of intracellular signaling is based on thesecond messengers derived ...
Protein kinase C effects include:• neurotransmitter release• cell growth & division• cell differentiation• glycogen hydrol...
CALMODULIN  Calmodulin binds directly with calcium ions to regulate the activity of  specific proteins.  Upon binding it u...
CALCIUM/CALMODULINCA2+ ions            CALMODULIN
#6: THE CALCIUM CALMODULIN COMPLEXREGULATES ENZYME ACTIVITY                             (enzyme)                  Ca+2    ...
SIGNAL AMPLIFICATION                       17-54
AmplificationCYTOPLASMIC RESPONSETO A SIGNAL.
cAMP and the Fight-or-Flight         Response; activation of PKAadrenaline                                                ...
CAFFEINE KEEPS YOU AWAKE BECAUSE IT 1.  Prevents the synthesis of     cAMP. 2.  Prevents the breakdown of     cAMP. 3.  In...
.ThanksGOOd   LUCK
09 02-12
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brief summary of receptors, g-protien, and 2nd messengers

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09 02-12

  1. 1. CELL SIGNALLING By: Khuram Aziz M.phill Biochemistry
  2. 2.  Overview of All lectures that you have learned Its brief description and animations
  3. 3. Cells also communicate by direct contact.1. Cell Junctions Signaling substances dissolved in the cell can pass freely from one cell to another2. Direct Contact Through molecules on the surface of the cell (embryonic development and the immune system)
  4. 4. COMMUNICATION BY DIRECTCONTACTWITH CELLS.
  5. 5. Local Chemical SignalingParacrineSecreting cell acts on nearby target cell bydischarging molecules into the extracellular fluidSynapticNerve cell releases neurotransmitter into synapses
  6. 6. DISTANT CELL COMMUNICATIONHormones signal target cells at much greaterdistances.Secreted into the body fluids, they reach allparts of the body.Only specific target cells are recognized andrespond
  7. 7. L LLocal and Distant Cell Communication In Animals. C O M M U N I C A T I
  8. 8. THE THREE STAGES OF CELL SIGNALINGFor a chemical signal to elicit a specificresponse, the target cell must possess asignaling system for the signal.1. Reception2. Transduction3. Response
  9. 9. OVERVIEW OF CELLSIGNALING.
  10. 10. Reception – signal (ligand) binds to aspecific cell surface protein.Transduction – binding results inconformation change of receptor. Thisinitiates transduction (one or manysteps)Response – almost any cellular activity
  11. 11.  Many signal molecules cannot pass freely through the plasma membrane Receptors are located on the plasma membrane These families are called: - G-protein linked receptors - tyrosine kinase receptors - ion channel receptors
  12. 12. Overview of the 3 Main Signal Transduction Pathways: e.g., neurotransmission e.g., cAMP mediated flight or fight response (glycogen breakdown, muscle contraction) e.g., regulatio n of many genes
  13. 13. A LIGAND-GATED ION-CHANNEL RECEPTOR.(important in nervous system)
  14. 14. Signal Transduction Themes: •intracellular 2nd messengers •changes in •Protein phosphorylation1. large or very polar enzyme activity extracellular ligand 4. protein •changes in (e.g., hormone) phosphorylation cytoskeletal organization 2. cell surface •changes in ion receptor permeabilty •activation of 3. intracellular 2nd replication messengers •regulation of transcription •Membrane depolarization
  15. 15. STEROID HORMONES: ACTION Blood Steroid 1 Most hydrophobic Cell surface receptor steroids are bound vessel hormone to plasma protein carriers. Only 2a unbound hormones Rapid responses 1 can diffuse into the target cell. 2 Protein 2 Steroid hormone carrier Nucleus receptors are Cytoplasmic typically in the Nuclear receptor cytoplasm or receptor nucleus. DNA 2a Some steroid hormones also Interstitial bind to mem- fluid brane receptors 3 that use second Endoplasmic messenger reticulum Transcription systems to Cell membrane produces mRNA create rapid 5 cellular 4 responses. New proteins Translation 3 The receptor- hormone complex binds to DNA 4 Activated genes create new 5 Translation produces new and activates or mRNA that moves into the proteins for cell processes. represses one or cytoplasm. more genes. Figure 7-7
  16. 16. STEROID HORMONES: ACTION Blood 1 Most hydrophobic steroids are bound vessel to plasma protein carriers. Only unbound hormones 1 can diffuse into the target cell. Protein carrier Nucleus Interstitial fluid Cell membrane Figure 7-7, step 1
  17. 17. STEROID HORMONES: ACTION Blood Steroid 1 Most hydrophobic steroids are bound vessel hormone to plasma protein carriers. Only unbound hormones 1 can diffuse into the target cell. 2 Protein 2 Steroid hormone carrier Nucleus receptors are Cytoplasmic typically in the Nuclear receptor cytoplasm or receptor nucleus. Interstitial fluid Cell membrane Figure 7-7, steps 1–2
  18. 18. STEROID HORMONES: ACTION Blood Steroid 1 Most hydrophobic Cell surface receptor steroids are bound vessel hormone to plasma protein carriers. Only 2a unbound hormones Rapid responses 1 can diffuse into the target cell. 2 Protein 2 Steroid hormone carrier Nucleus receptors are Cytoplasmic typically in the Nuclear receptor cytoplasm or receptor nucleus. 2a Some steroid hormones also Interstitial bind to mem- fluid brane receptors that use second messenger systems to Cell create rapid membrane cellular responses. Figure 7-7, steps 1–2a
  19. 19. STEROID HORMONES: ACTION Blood Steroid 1 Most hydrophobic Cell surface receptor steroids are bound vessel hormone to plasma protein carriers. Only 2a unbound hormones Rapid responses 1 can diffuse into the target cell. 2 Protein 2 Steroid hormone carrier Nucleus receptors are Cytoplasmic typically in the Nuclear receptor cytoplasm or receptor nucleus. DNA 2a Some steroid hormones also Interstitial bind to mem- fluid brane receptors 3 that use second messenger systems to Cell create rapid membrane cellular responses. 3 The receptor- hormone complex binds to DNA and activates or represses one or more genes. Figure 7-7, steps 1–3
  20. 20. STEROID HORMONES: ACTION Blood Steroid 1 Most hydrophobic Cell surface receptor steroids are bound vessel hormone to plasma protein carriers. Only 2a unbound hormones Rapid responses 1 can diffuse into the target cell. 2 Protein 2 Steroid hormone carrier Nucleus receptors are Cytoplasmic typically in the Nuclear receptor cytoplasm or receptor nucleus. DNA 2a Some steroid hormones also Interstitial bind to mem- fluid brane receptors 3 that use second messenger Transcription systems to Cell membrane produces mRNA create rapid cellular 4 responses. 3 The receptor- hormone complex binds to DNA 4 Activated genes create new and activates or mRNA that moves into the represses one or cytoplasm. more genes. Figure 7-7, steps 1–4
  21. 21. STEROID HORMONES: ACTION Blood Steroid 1 Most hydrophobic Cell surface receptor steroids are bound vessel hormone to plasma protein carriers. Only 2a unbound hormones Rapid responses 1 can diffuse into the target cell. 2 Protein 2 Steroid hormone carrier Nucleus receptors are Cytoplasmic typically in the Nuclear receptor cytoplasm or receptor nucleus. DNA 2a Some steroid hormones also Interstitial bind to mem- fluid brane receptors 3 that use second Endoplasmic messenger reticulum Transcription systems to Cell membrane produces mRNA create rapid 5 cellular 4 responses. New proteins Translation 3 The receptor- hormone complex binds to DNA 4 Activated genes create new 5 Translation produces new and activates or mRNA that moves into the proteins for cell processes. represses one or cytoplasm. more genes. Figure 7-7, steps 1–5
  22. 22. Please note that due to differingoperating systems, some animationswill not appear until the presentation isviewed in Presentation Mode (SlideShow view). You may see blank slidesin the “Normal” or “Slide Sorter” views.All animations will appear after viewingin Presentation Mode and playing eachanimation. Most animations will requirethe latest version of the FlashPlayer, which is available athttp://get.adobe.com/flashplayer. 17-22
  23. 23. THE STRUCTURE OF A G-PROTEIN –LINKEDRECEPTOR.
  24. 24. RECEPTORS THAT ACTIVATE GPROTEINS 17-24
  25. 25. Please note that due to differingoperating systems, some animationswill not appear until the presentation isviewed in Presentation Mode (SlideShow view). You may see blank slidesin the “Normal” or “Slide Sorter” views.All animations will appear after viewingin Presentation Mode and playing eachanimation. Most animations will requirethe latest version of the FlashPlayer, which is available athttp://get.adobe.com/flashplayer. 17-25
  26. 26. ANOTHER RECEPTOR – G PROTEIN CYCLE
  27. 27. CAMP AS ASECONDMESSENGER.
  28. 28. c-AMP: a second messenger
  29. 29. OVERVIEW- GENERAL STRUCTURE Lyase Enzyme that converts ATP to cAMP Interacts with g proteins and receptors 1064-1353 amino acids long 120-150 kilodaltons
  30. 30. GENERAL STRUCTURE CONT’D 10 mammalian isoforms  All membrane bound  60% similarity  50%-90% in cytoplasmic regions
  31. 31. PRIMARY STRUCTURE The main structural features of mammalian adenylyl cyclases M1/M2: 2 sets 6 transmembrane spans C1a/C1b: large cytoplamic domains (360-390 amino acids) C2a/C2b: large cytoplasmic domains (255-330 amino acids)  Most highly conserved sequence in all isoforms  50% similar; 25% identical N terminus and C terminus
  32. 32. ROLE OF CYCLIC AMP Step 1: activates protein kinases Step 2: protein kinases phosphorylate substrate proteins Step 3: activated substrate proteins regulate hormone production
  33. 33. G-protein Mediated cAMPsynthesis a a g b ATP GTP GDP cAMP +PPi GTPWhen the [hormone] drops… g a b GTP GDP ATP Pi cAMP +PPi
  34. 34. ADENYLYL CYCLASE RECEPTORGDP GTP
  35. 35. G PROTEINS THAT INTERACT WITHADENYLATE CYCLASE 17-35
  36. 36. WHAT DOES IT DO?
  37. 37. Please note that due to differingoperating systems, some animationswill not appear until the presentation isviewed in Presentation Mode (SlideShow view). You may see blank slidesin the “Normal” or “Slide Sorter” views.All animations will appear after viewingin Presentation Mode and playing eachanimation. Most animations will requirethe latest version of the FlashPlayer, which is available athttp://get.adobe.com/flashplayer. 17-37
  38. 38. RECEPTORS THAT DIRECTLY ALTERTHE ACTIVITY OF INTRACELLULARMEDIATOR 17-38
  39. 39. G-protein mediated signal transduction ismediated by several 2nd messengers: Adenylate cyclase cAMP protein kinase A SER Phospholopase C IP3 Ca++ Ultimate (inositol triphosphate) effects DAG (diacyl glycerol) protein kinase C
  40. 40. 2ND MESSENGERS: IP3 AND DAG PLC= Phospholipase C PLC- activePhosphatidylinositol- 4,5 biphosphate=(PIP2) is a membrane phospholipid cleaved into free IP3 and membrane bound DAG by phospholipase C. (Ch.7) (Ch.12)
  41. 41. HYDROLYSIS OF PIP2One of the most widespread pathways of intracellular signaling is based on thesecond messengers derived form PIP2phosphatidylinositol 4,5-bisphosphate
  42. 42. LE 11-12_1 EXTRACELLULAR Signal molecule FLUID (first messenger) G protein DAG GTP G-protein-linked PIP2 receptor Phospholipase C IP3 (second messenger) IP3-gated calcium channel Endoplasmic Ca2+ reticulum (ER) CYTOSOL
  43. 43. LE 11-12_2 EXTRACELLULAR Signal molecule FLUID (first messenger) G protein DAG GTP G-protein-linked PIP2 receptor Phospholipase C IP3 (second messenger) IP3-gated calcium channel Endoplasmic Ca2+ reticulum (ER) Ca2+ (second CYTOSOL messenger)
  44. 44. LE 11-12_3 EXTRACELLULAR Signal molecule FLUID (first messenger) G protein DAG GTP G-protein-linked PIP2 receptor Phospholipase C IP3 (second messenger) IP3-gated calcium channel Various Cellular Endoplasmic Ca2+ proteins re- reticulum (ER) activated sponses Ca2+ (second CYTOSOL messenger)
  45. 45. Ca2+ pool can be affected in 2 ways:1. Ligand binding to a calcium ion channel2. Activation of IP3 signaling pathway
  46. 46. G PROTEINS THAT OPEN CALCIUM IONCHANNELS 17-46
  47. 47. Please note that due to differingoperating systems, some animationswill not appear until the presentation isviewed in Presentation Mode (SlideShow view). You may see blank slidesin the “Normal” or “Slide Sorter” views.All animations will appear after viewingin Presentation Mode and playing eachanimation. Most animations will requirethe latest version of the FlashPlayer, which is available athttp://get.adobe.com/flashplayer. 17-47
  48. 48. ligand -gated(IP3) ligand -gated (Ca2+ ) P-type Ca2+ pump P-type Ca2+ pump voltage -gated
  49. 49. HYDROLYSIS OF PIP2One of the most widespread pathways of intracellular signaling is based on thesecond messengers derived form PIP2phosphatidylinositol 4,5-bisphosphate
  50. 50. Protein kinase C effects include:• neurotransmitter release• cell growth & division• cell differentiation• glycogen hydrolysis• fat synthesis Phospholipase C-mediated effects:•Liver glycogen breakdown (vasopressin)•Pancreatic amylase secretion (acetylcholine)•Platelet aggregation (thrombin)
  51. 51. CALMODULIN Calmodulin binds directly with calcium ions to regulate the activity of specific proteins. Upon binding it undergoes a conformational change allowing binding of other proteins, activating or inactivating themThe protein Calmodulin withcalcium binding.Calcium: bluealpha-Helices: orangebeta-sheets: green.
  52. 52. CALCIUM/CALMODULINCA2+ ions CALMODULIN
  53. 53. #6: THE CALCIUM CALMODULIN COMPLEXREGULATES ENZYME ACTIVITY (enzyme) Ca+2 triggers conformation change CCC
  54. 54. SIGNAL AMPLIFICATION 17-54
  55. 55. AmplificationCYTOPLASMIC RESPONSETO A SIGNAL.
  56. 56. cAMP and the Fight-or-Flight Response; activation of PKAadrenaline Liver cell ATP inactive active cAMP adenylyl cyclase p inactive active cAMP inactive active glycogen inactive active phosphorylase p phosphorylase protein kinase kinase A glycogen glucose-1-phosphate amplification
  57. 57. CAFFEINE KEEPS YOU AWAKE BECAUSE IT 1. Prevents the synthesis of cAMP. 2. Prevents the breakdown of cAMP. 3. Inactivates the enzyme protein kinase A. 4. Inhibits the enzyme glycogen phosphorylaseCaffeine inhibits the enzymephosphodiesterase, whichnormally breaks down cAMP.
  58. 58. .ThanksGOOd LUCK

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