receptors/signaling

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Author:
lintyone
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104332
Filename:
receptors/signaling
Updated:
2011-09-25 23:37:31
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ibhs2a
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IBHS.E2.Bryant
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  1. Cell membrane is made up of:
    • phospholipids
    • cholesterol
    • proteins
  2. membrane transports
    • passive (facilitated)
    • active (primary, secondary)
  3. types of communication
    • intercellular signaling
    • intracellular signaling
  4. adrenergic receptors
    • alpha 1 (vasoconstriction)
    • alpha 2
    • beta 1 (increase heart rate)
    • beta 2 (bronchodilation)
  5. Cellular signaling
    intercellular signaling
    • cell-to-cell/direct
    • autocrine
    • paracrine
    • nervous/synaptic
    • endocrine
  6. Cellular signaling
    intracellular signaling
    Ligand

    aka chemical messenger or 1st messenger
  7. intracellular signaling
    ligand
    • extracellular mol that binds receptor
    • can activate or inhibit intracell.signal.

    2 types: endogenous, exogenous
  8. Endogenous ligand
    produced by body

    ex. hormones, paracrine factors, etc.
  9. Exogenous ligand
    administered to body

    ex. drugs, toxins
  10. Ligand activity
    Efficacy
    ability of ligand to initiate cellular effect
  11. Ligand activity
    Agonist
    most are agonists!

    • ligand that has both receptor affinity & efficacy
    • (binds to receptor and initiates cell effect)

    endo/exogenous
  12. Ligand activity
    antagonist
    • ligand that has receptor affinity but lacks efficacy
    • (blocks access of agonist) -->competitive antagonist
  13. endo/exogenous
  14. Receptors
    • located in cm or intracell. mol
    • binds ligand
    • mods signal transduction pathway (can turn on/off)
  15. signal transduction pathway
    aka intracell. signaling or 2nd msgr

    molecular chain of events, mods cell activity
  16. modifying cell activity via signal trans.pthwy
    enzymes
    • kinase (phosphorylation)
    • phosphotase (dephosphorylation)
  17. modifying cell activity via signal trans.pthwy
    cell activities
    • opening ion channels
    • initiate gene transcription
    • initiate gene translation
    • protein synthesis
    • secretion of proteins
  18. Receptor regulation by ligands
    Desensitization
    due to continuous or repeated exposure
  19. Types of desensitization
    • receptor sequestration
    • receptor down-regulation
    • receptor inactivation
    • inactivation of signaling protein
    • production of inhibitory protein
  20. receptor sequestration
    if not as many receptors on cell surface then not much activity
  21. receptor down-regulation
    • decrease gene transcription of receptor
    • due to prolonged increased levels of ligand signaling
  22. receptor inactivation
    • turns off!
    • receptors get phosphorylated
  23. inactivation of signaling protein
    • turns off!
    • something binds to receptor bug signal is turned off
  24. production of inhibitory protein
    signaling causes synthesis of some protein that inhibits signal

    similar to neg.fdbk
  25. up-regulation
    • increase gene transcripton of receptor
    • due to prolonged decreased lvls of ligand
  26. is activation of receptor leading to down-regulation?
    • OVERACTIVATION does!
    • (or underactivation)

    form of neg.fdbk
  27. Receptor classes
    • cell membrane receptors
    • intracellular receptors
  28. Types of cell membrane receptors
    • GPCRs
    • Enzyme-linked receptors/kinase receptors
    • ion channel-linked receptors
  29. types of intracellular receptors
    • steroid receptors
    • thyroid receptors

    located on cytoplasm or nucleus
  30. ion channel-linked receptor's ligand
    neurotransmitters

    takes milliseconds to reach target
  31. GPCR's ligand
    • a mix
    • any type of signaling molecule

    • activation of enz act. other proteins
    • takes seconds to happen
  32. ligand for kinase-linked receptors
    • cytokines
    • growth factors

    • can act as paracrine hormone, etc. depends where in body
    • takes hours to reach target
  33. ligand for intracellular receptors
    hormones

    • ex. steroid hormones
    • takes longest to reach target (hours)
  34. endogenous macromolecules that bind drug to elicit therapeutic outcome
    • receptors
    • enzymes
    • nucleic acids
    • ligands
  35. drug targets
    receptors
    CM or intracellular receptor
  36. drug targets
    enzymes
    • cm
    • intracellular
    • extracellular
  37. drug targets
    nucleic acids
    • DNA/RNA
    • ribosomes
  38. drug targets
    ligands
    • hormone
    • paracrine
  39. GPCRs
    • aka metabotropic receptors (nerv.sys)
    • aka 7-transmembrane spanning receptor
  40. GPCRs
    signaling
    • couples (associates) with G proteins (Gs, Gi, Gq)
    • leads to production of 2nd msgrs
  41. GPCRs: intracell. signal.
    General scheme
    • receptors
    • 1st msgrs (ligands)
    • transducers/effectors (trans- usually Gproteins)
    • 2nd msgrs
    • physiological response
  42. How do GPCRs work?
    • GPCRs couple w/G proteins
    • G protein acts as transducer, activates effector (Ac)
    • 2nd msgrs produced (amplification)
  43. G proteins are heterotrimeric
    (contains 3 subunits)
    • alpha
    • beta
    • gamma
  44. How do G proteins work?
    activated when bound to GTP

    • have intrinsic GTPase activity
    • (converts GTP->GDP)
    • (Gprotein inactive when GDP bound)
  45. GPCR signaling
    Gs
    • -Ligands bind receptor
    • -Gs activated
    • -alpha subunit dissociates away from beta, gamma

    -AC stimulated, converts ATP->cAMP
  46. GPCR signaling: Gs
    cAMP
    activates cAMP-dependent PKA
  47. GPCR signaling: Gs
    PKA
    • 2 catalytic subunits & 2 regulatory subunits
    • phosphorylates other mol
    • activates PDE
  48. GPCR signaling: Gs
    activated PKA
    • mediates effects in cell, occur in seconds
    • can enter nucleus and regulate gene trans. by activating CREB
  49. GPCR signaling: Gs
    CREB
    • cAMP response element binding protein
    • recognizes cAMP response element which stimulates transcrptn of target genes
  50. GPCR signaling: Gs
    stimulates AC
  51. GPCR signaling: Gi
    inhibits AC
  52. GPCR signaling
    PDEs
    phosphodiesterases

    • - breakdown cAMP (to 5' AMP, so cant act as 2nd msgr)
    • - activated by PKA
  53. GPCR signaling: Gq
    • diff signal transduction pthwy
    • effector = Phospholipase C (PLC
    • IP3 or Ca2+ can be 2nd msgrs
  54. Gq
    • -signal mol binds
    • -GPCR activated
    • -GDP->GTP
    • -activated Gq protein
    • -binds and activates effector (PLC)
    • -phos. PLC --> PI 4,5bisphosphate and Ip3

    -IP3 binds to receptor on ER, Ca in cell & increased

    • -PI4,5bisphos. -> DAG
    • -DAG binds act. protein kinase C
  55. example of Gq
    • smooth muscle cells in blood vessels
    • increase in calcium causes contraction
    • bc intracellular signals increase!
  56. Gs
    • alpha subunit
    • activates AC
    • activates calcium channels
  57. Gi
    • alpha subunit
    • inhibits AC

    • beta/gamma subunit
    • activate potassium channels
  58. Gq
    • alpha subunit
    • activates PLC
  59. Why are GPCRs good drug targets?
    • -->location
    • cell surface receptor- no need to go inside to effect

    • -->ratio
    • 1 ligand bind= multiple G proteins can activate
  60. GPCRs and Drug Industry
    most successful drug target
    • 25-30% top 100 Rx target GPCRs
    • 50-70% of Rxs target GPCRs
    • 75% of all CNS Rxs target GPCRs
  61. GPCRs and Drug Industry
    Saturated?
    • 20-80% diff GPCRs r targeted by Rxs
    • ~80% GPCRs w/known ligands r not Rx targets
    • 140 orphan receptors still w/o ligands
  62. Types of GPCR disorders
    • mutations
    • processing error
    • antibodies
    • toxins
  63. GPCR disorders
    mutations
    • - incorrect gene seq = incorrect protein seq & receptor - shape is altered
    • - can result in permanent OFF or ON

    • ex. inherited hypocalciuric hypercalcemia
    • (receptor lose ability to sense Ca properly)
  64. GPCR disorders
    processing error
    • - gene is OK
    • - protein misfolds during processing
    • - receptor shape altered

    • - can result in permanent OFF or ON
    • ex. blindness caused by altered rhodopsin receptor
  65. GPCR disorders
    antibodies
    • - structure of receptor is OK
    • - body producing antibodies that stick to it
    • - can turn receptor OFF or ON

    ex. graves disease
  66. GPCR disorders
    toxins
    • struct./fn receptor is OK
    • toxins interfering w/signaling of G Proteins
    • Can turn receptor sig. OFF or ON
    • ex. cholera vs. pertussis
  67. Bacterial toxins that alter G protein activity
    Cholera toxin
    • (intestinal infection)
    • abolish GTPase activity in Gs
    • (increased cAMP lvl)
    • excess Cl lost in lumen, H2O follows
    • Diarrhea, dehydration
  68. Bacterial toxins that alter G protein activity
    Pertussis toxin
    • (whooping cough)
    • locks Gi in GDP state
    • Decrease activity of phagocytic immune cells
    • paralyzes respiratory cilia
    • results: infection, inflam., coughing
  69. Enzyme-linked receptors
    or Kinase receptors
    • aka Tyrosine Kinase Receptor
    • aka Serine/Threonine Kinase Receptors
  70. Enzyme-linked receptors
    Receptor structure
    • binding domain (on extracell. side)
    • transmembrane region
    • kinase domain
    • autophosphorylated region
  71. Enzyme-linked receptors
    Receptor activation
    • ligand binds
    • receptors dimerize
    • receptors autophosphorylate
  72. Enzyme-linked receptors
    endogenous ligands
    • insulin (hormone)
    • GFs (paracrine, hormone)
    • Cytokines (paracrine, hormone)
  73. endogenous ligands
    insulin
    • promotes glu & aa uptake into cells
    • promotes DNA rep & protein synthesis
  74. endogenous ligands
    growth factors
    • +/- cell replication
    • +/- cell differentiation
  75. endogenous ligands
    cytokines
    • +/- cell replication
    • +/- cell differentiation
    • +/- inflammation
  76. enzyme linked receptor signaling
    • kinase receptor
    • kinase receptor signaling
    • abnormal kinase receptor signaling
  77. enzyme linked receptor signaling
    kinase receptor
    • dimerization
    • autophosphorylation
  78. enzyme linked receptor signaling
    kinase receptor signaling
    • activation of intracell. kinases
    • (lots of phosphorylation, often cascades)

    • activation of intracell. proteins
    • (Ras activation)
  79. enzyme linked receptor signaling
    abnormal kinase receptor signaling
    • can result in cancer
    • mutated ras found in 25% of all cancers
  80. RAS
    • -small G protein
    • -made of 1 subunit (monomeric)
    • -has no intrinsic GTPase activity
    • -activates MAP kinase cascade
    • -result: turns on gene trnscrptn/translatn

    --> cell growth & proliferation
  81. ion channel-linked receptors
    • aka ligand-gated ion channel
    • aka ionotropic receptor
  82. ion channel-linked receptors
    signaling
    • ligand binds
    • opens channel
    • ion diffusion allowed
  83. ion channel-linked receptors
    endogenous ligands
    • Ach = Na+ in
    • Serotonin (5HT3) = cations
    • glutamate (NMDA) = cations
    • GABAA = Cl in
  84. intracellular receptors
    • aka nuclear hormone receptors (NHR)
    • aka cytosolic receptors
  85. intracellular receptors
    signaling
    • ligand diffuse thru membrane
    • bind in cytosol/nucleus
    • complex migrates to nucleus
    • affects gene transcrp/transltn
  86. intracellular receptors
    endogenous ligands
    • glucocoritcoids (corticosteroids)
    • estrogen, progesterone, androgens
    • thyroid hormones
  87. What is a ligand?
    primary messenger
  88. what is the diff btwn agonist and antagonist?
    • agonist = has receptor affinity & efficacy
    • antag = has only affinity
  89. what are the main types of intercellular signaling?
    • autocrine
    • paracrine
    • nervous
    • cell-to-cell
    • endocrine (neuroendorcrine)
  90. what are the 3 types of cell membrane receptors?
    • GPCRs
    • ion channel receptors
    • enzyme-linked receptors
  91. what are the 3 main classes of G proteins?
    • Gs
    • Gi
    • Gq
  92. what is the mechanism of cholera toxin?
    • inhibits GTPase activty
    • increase cAMP
    • -Gs protein
  93. why is overactivation of Ras associated with cancer?
    ras inovolved in activation of growth pathway
  94. what types of molecules bind to intracellular receptors?
    lipophillic

    ex. steroid hormones

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