PHRD5015 Mechanisms of Disease - Module 1 (Movement of information and molecules across the cell mem

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PHRD5015 Mechanisms of Disease - Module 1 (Movement of information and molecules across the cell mem
2013-09-16 14:50:59
mechanisms disease

mechanisms of disease
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  1. phospholipid constituents
    • glycerol
    • fatty acids
    • polar head group
  2. charge of fatty acids in phospholipid
    no charge
  3. portion of phospholipid with charge
    head group
  4. form hydrophobic barrier which keeps charged molecules from crossing from 1 side of the membrane to the other
    fatty acids
  5. 3 properties of phospholipid barriers
    • 1) spontaneously form in aqueous environment
    • 2) forces create barriers to movement
    • 3) membranes are 2D solutions
  6. forces that create barriers to movement through phospholipid bilayers
    • Van der Waals forces (fatty acids)
    • electrostatic forces (polar head groups and water)
  7. all possible hydrogens are present in a fatty acid
  8. some carbons have double bonds (less hydrogens) in a fatty acid
  9. type of fatty acid that makes a membrane MORE fluid

    (kinks in carbon chain)
  10. types of fatty acid that makes membrane STIFFER
  11. other components of cell membrane
    • 1) sphingolipids
    • 2) cholesterol
  12. use sphingosine as the backbone instead of glycerol
  13. parent compound for all spingolipids
  14. type of sphingolipid that contains sugars instead of a head group
  15. sphingolipid structurally vital for the assembly of lipid rafts
  16. type of sphingolipid that determines blood groups
  17. 3 ganglioside diseases
    • 1) Tay-Sachs
    • 2) Guillain-Barre
    • 3) Alzheimer's
  18. portion of cholesterol that points outward in the membrane
    hydroxyl group
  19. breaks up interactions between fatty acids in the membrane
  20. created by membrane proteins to create a diffusion barrier
    tight junctions
  21. disease where the buildup of excess cholesterol leads to damage of blood vessels
  22. 4 general types of signaling
    • 1) direct cell-cell
    • 2) endocrine
    • 3) paracrine
    • 4) autocrine
  23. -signal is distributed throughout the body
    -specificity occurs at the receptor level
    endocrine signaling
  24. -method to keep a signal localized
    -regulation occurs at the level of generating the signal
    paracrine signaling
  25. example of a paracrine signal
    nitric oxide from vascular endothelial cells act on vascular smooth muscle
  26. -self-stimulating signaling
    -provides positive feedback loop
    autocrine signaling
  27. example of autocrine signaling
    T-cell activation
  28. signal transduction steps (5)
    • 1) release 1st messenger
    • 2) transport to site
    • 3) recognition/binding
    • 4) transduction/amplification
    • 5) cell response
  29. causes fusion of vesicles with the surface of the cell
    increase in intracellular Ca2+
  30. 3 types of messenger release
    • 1) cleavage from membrane
    • 2) continuous release
    • 3) regulated release
  31. regulated release
    signals only released at certain times, even though they are always present in vesicles
  32. allows for targeting of signals to specific cells without dilution
    portal systems
  33. 4 classes of receptors
    • 1) intracellular
    • 2) ion channels
    • 3) G coupled protein
    • 4) RTKs
  34. example of intracellular receptor
    steroid hormone receptors

    hormone diffuses across membrane -> receptor activated -> receptor binds DNA to activate transcription
  35. type of receptor ACh receptor is
    ion channel
  36. glucose sensor in the cell
  37. protein that migrates along the membrane to its target when activated
    G protein
  38. G protein that activated adenylyl cyclase
  39. activates Gs
    GDP -> GTP
  40. catalyzes formation of cAMP
    adenylyl cyclase
  41. activated by cAMP in B-adrenergic pathway
  42. physiological functions of the B-adrenergic receptor (5)
    • 1) increase heart rate
    • 2) increase BP
    • 3) decrease airway resistance
    • 4) increase gluconeogenesis
    • 5) increase muscle glycogen breakdown
    • **fight or flight response
  43. converts cAMP to AMP
  44. how cAMP activates PKA
    removes inhibitory protein
  45. physiological fcns of mAChR
    • 1) decrease HR
    • 2) decrease BP
    • 3) increase blood flow to gut
    • 4) decrease muscle glycogen breakdown/gluconeogenesis

    **rest/digest response
  46. nitric oxide receptor
    guanylyl cyclase
  47. converts GTP to cGMP
    guanylyl cyclase
  48. promotes relaxation of smooth muscle cells
  49. molecular memory switch
  50. activates CaMKII
  51. EGFR cascade
    EGFR receptor -> intracellular phosphorylation -> Grb2/Sos bind -> Ras binds to Sos -> Ras releases GDP and binds GTP -> Raf1 activated -> MAPK cascade
  52. protein that is tethered to the membrane with a covalently attached lipid group (farnesyl group)
  53. G protein-like protein that promotes cell proliferation
  54. MAPK cascade
    Raf1 -> Mek1 -> MAPK
  55. major determinants of pharmacokinetic, safety, and efficacy profiles of drugs
    membrane transporters
  56. 2 major superfamilies of of membrane transporters
    • 1) solute carrier (SLC) superfamilies
    • 2) ATP-binding cassette (ABC)
  57. SLC transporter
    influx of solutes
  58. ABC transporter
    efflux of xenobiotics
  59. transports solute molecule by undergoing a reversible change in conformation
    passive transporters
  60. 2 types of active transporters
    • 1) primary-active transporters
    • 2) secondary-active transporters
  61. transporter coupled to ion pumps
    secondary active transporters
  62. aids drug transport
    SLC transporter
  63. used to exclude drugs from their site of action
    ABC transporter
  64. structure of ABC transporter
    2 ATP binding domains (cassettes) that dimerize when ATP bound -> different face of transporter opens
  65. -ABC transporter whose role is to pump out toxins
    -overexpressed in cancers
  66. P-gp substrates (2)
    • 1) doxorubicin
    • 2) irinotecan
  67. ABC transporter that functions in the secretion of vitamins into breast milk
    breast cancer resistant protein (BCRP transporter)
  68. CFTR
    • ABC transporter
    • ion channel
    • inactivated in cystic fibrosis -> reduced Cl & Na secretion -> thick mucus
  69. where vesicles are often formed at
    clathrin coated pits
  70. 3 vesicle cage proteins
    • 1) clathrin
    • 2) COPI
    • 3) COPII
  71. multi-subunit protein that binds to both clathrin and to integral membrane proteins
  72. its amino acid motif for binding is found on the cytoplasmic side
  73. through this protein, clathrin begins to induce clustering of integral membrane proteins
  74. important sorting point for incoming biomolecules
    early endosome
  75. how acidic environment is created in endosomes
    proton pump (H+ATPase)
  76. how LDL binds to LDL receptor
    • 1) newly synthesized LDL receptors diffuse to a newly forming clathrin coated pit
    • 2) cytoplasmic tail of LDL receptor binds to adaptin via adaptin binding motif
  77. where LDL is released
    endosomal compartments
  78. mutation involved in familial hypercholesterolemia (FH)
    • LDL receptor
    • disruption in receptor mediated endocytosis of LDL
  79. protein that binds iron ions and brings them to the cell