Receptors

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XQWCat
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311777
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Receptors
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2015-11-23 12:02:29
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Block II
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receptors, week II block II
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  1. receptor type that binds ligands reversibly with high affinity and specificity
    recognition
  2. receptor type, structural-dependent, converts binding into response
    transduction
  3. receptor-binding interaction criteria; ligand is structurally complementary (high-affinity)
    specificity
  4. finite number of receptors per cell (shown in binding curve). Receptor-binding interaction criteria
    Saturability
  5. receptor-binding interaction criteria; ligand must dissociate unchanged after binding
    reversibility
  6. receptor-binding interaction criteria; ligand must dissociate unchanged after binding
    partial agonist
  7. ligands that produce the maximum response at the receptor.
    full agonist
  8. bind at the active site but do not cause activation of receptor
    competitive antagonist
  9. bind to receptor at different site and prevent activation
    noncompetitive antagonist
  10. ligand that activates receptor to cause a physiologic response
    agonist
  11. maximal response is possible with only a fraction of total receptors are occupied
    spare receptors
  12. ligand that does not actiate the receptor and interferes with response produced by an agonist
    antagonist
  13. ligand that prevents the binding of another ligand to the receptor
    inhibitor
  14. dose of agonist that produces a half-maximal effect or response
    ED50
  15. concentration of agonist that produces half-maximal inhibition
    IC50
  16. Describe the role of focal adhesion kinase (FAK) in the regulation of cell motility
    The boss of cell motility. Command and control. Recruited by integrins, phosphorylates tyrosine to dock proteins.
  17. List the key steps in cellular migration
    • ECM degraded by proteases (serine and metalloproteinases
    • Actin and membrane sent out in front
    • Integrin-mediated attachment for traction (focal adhesions)
    • Recruit focal adhesion kinase, which runs the entire move
    • Tyrosine phosphorylation by FAK creates docking sites
    • Attachments at rear disassembled for movement
  18. How are junctional complexes organized?
    Most apical are occluding, then adherens, desmosomes, gap junctions, cell-matrix anchoring junctions (actin-linked and hemidesmosomes)
  19. Explain how cells alter permeability at occluding junctions.
    Long rows of claudins and occludins control ion-selectivity, change permeability depending on circumstances (bladder in blocked cats becomes permeable to potassium)
  20. List the two primary functions of occluding junctions.
    • Seal between adjacent cells (Semi-permeable barrier to solute diffusion)
    • Keep proteins on appropriate side (basal vs apical) of polarized cells
    • aka Tight junctions
  21. Define “epithelial to mesenchymal transition” and explain how it is regulated.
    • Disassemble from parent epithelium, change to mesenchymal and migrate away individually, as in a wound
    • Regulated by transcription factors like Twist, tells the cell to stop expressing cadherins
  22. Explain how the beta-catenin functions (hint: two roles)
    • At adherens, serves as an anchor protein
    • In the nucleus, serves as a nuclear transcription factor.
    • Location determines function.
    • Mislocation is cancer.
  23. Describe the difference between the two cell-cell anchoring junctions.
    • Adherens is more apical, linked at actin cytoskeleton. Adhesion belt
    • Desmosome is more basal, connected to intermediate filaments and hemidesmosomes
  24. List the four classes of anchoring junctions.
    • Cell-cell:
    • Adherens junctions
    • Desmosomes
    • Cell—matrix:
    • Actin-linked
    • hemidesmosome
  25. List the two primary functions of anchoring junctions.
    • Mechanically attach cells to neighboring cells
    • Transmit physical forces across multiple cells
  26. List the two major classes of cell adhesions that allow cells to form an epithelium.
    • Cell-cell adhesions (adherens junctions and desmosomes)
    • Cell-matrix adhesions (actin-linked cell-matrix adhesions, hemidesmosomes)
  27. List four functions of basement membranes.
    • Scaffold for epithelial cells, attach to connective tissue
    • Determine architecture of epithelial organs
    • Scaffold for tissue regeneration
    • Molecular filter
  28. types of cell signaling (3-4)
    • contact-dependent
    • paracrine/autocrine(synaptic), endocrine
  29. examples of G-protein receptors
    Beta-adrenergic, rhodopsin, olfactory
  30. How G-protein receptors transmit signal across membrane
    7 transmembrane helixes, conformational changes
  31. how enzyme-coupled receptors transmit signal across membrane
    dimerization required (caused by ligand)
  32. steriod receptors
    hang out in cytoplasm, bind to ligand, release chaperones, cross into nucleus, bind, homodimerize.
  33. 2 properties that define receptors
    • recognition (reversible, specific)
    • transduction (binding creates a response)
  34. difference between receptors and enzymes
    receptors leave ligand unchanged
  35. 3 criteria for recognition/binding of receptors
    • specificity (complementary)
    • saturability (finite number of receptors per cell)
    • reversibility (ligand dissociates unchanged)
  36. affinity vs KD
    • high affinity = low KD
  37. spare receptors
    when classical theory was disproved, and amplification caused maximum response at 10% saturation, demonstrating that 90% of receptors were "spare".
  38. 5 ways cells can "turn off" their response to prolonged signaling
    • receptor sequestration (endosome)
    • receptor down-regulation (lysosome)
    • receptor inactivation (feedback loop)
    • inactivation of signaling protein (feedback loop to protein that bonds to receptor)
    • production of inhibitory protein
  39. things that can/do happen in desensitization
    • ligand-gated and voltage-gated ion channels close
    • G protein receptors phosphorylated to inactive form by protein kinase A, bind arrestin
    • usually/often reversible
  40. things that can/do happen in down-regulation
    • G protein receptors (beta adrenergic) endocytosed after phosphorylation.  Bind arrestin, then ubiquitination.  
    • Sometimes/often not reversible.
  41. upregulation
    respond to antagonists by increasing numbers of receptors, usually iatrogenic.
  42. examples of G protein receptors
    rhodopsin, beta-adrenergic
  43. regulators of G-proteins
    • GTPase Activating Proteins (GAPs)
    • Regulators of G Protein Signaling (RGS)
    • endocytosis of receptor
  44. beta adrenergic path
    epinephrine -- beta adrenergic receptor -- G binds -- GDP becomes GTP on alpha -- alpha leaves, finds adenylyl cyclase -- ATP becomes cAMP -- activates A kinase -- Ca2+ channels open
  45. Rhodopsin path
    light activates rhodopsin -- G binds -- GDP becomes GTP on alpha -- alpha leaves -- cGMP phosphodiesterase (PDE) -- hydrolysis of cGMP -- retinal Na channels close, hyperpolarization of membranes
  46. What happens at the N terminal
    glycosylation and ligand binding
  47. what happens at the C terminal
    phosphorylation and palmoitoylation
  48. Examples of growth factor tyrosine kinases
    • epidermal growth factor (EGF) receptor
    • insulin receptor, insulin-like growth factor receptor, platelet-derived growth factor (PDGF)
    • Neu/ErbB2/HER2 (CANCER), fibroblast growth factor (FGF), hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF)
  49. structure of tyrosine kinases
    • 2 hydrophilic domains: extracellular (binds polypeptide growth factor) and cytoplasmic (tyrosine kinase active site)
    • ONE transmembrane helix, so dimerize to become active.
  50. Insulin receptor general mechanism
    • dimerize, alpha-2-beta-2 tetrameric subunit arrangement (2 alpha insulin receptors extracellularly, two tyrosine kinase beta subunits connected intracellularly.  
    • trans-phosphorylation activates insulin receptor to phosphorylate IRS-1
  51. Platelet-derived growth factor (PDGF)
    • acts on blood vessel wall at injury
    • homodimer or heterodimer (AA, AB, BB)
    • kinase domain insert (KI) sequence between trans-phosphorylation and ATP binding sites.
  52. Nuclear receptors
    (hydrophobic) ligand-regulated transcription factors.
  53. How G proteins, tyrosine kinases and nuclear receptors work together (path)
    G protein -- adenlylyl cyclase -- increase cAMP -- protein kinase A -- phosphorylation -- cAMP Response Element Binding Protein (CREB) -- tyrosine kinase -- cascade -- gene transcription (+/-)
  54. steroid receptor pathway
    steroid ligand -- receptor in cytoplasm -- conformational change, dissociation of chaparones, reveal DNA binding site -- nucleus -- homodimer, bind to DNA (palindromic) -- coactivators
  55. RXR pathway (nuclear)
    ligand dissociates from carrier, enters cell, enters nucleus, bind to already-assembled heterodimer already bound to DNA.  Binds.  Release of corepressors and binding of coactivators.
  56. RXR examples
    thyroid hormone receptor, vitamin D receptor, retinoic acid receptor, etc.
  57. 4 receptor domains of Nuclear receptors
    • Regulatory domain, binds coregulators (activators or repressors), responsibe for effects on genes.  Most varied region.  
    • DNA-binding domain, "zinc fingers" to decide which genes
    • Hinge domain, nuclear localization, dimer formation
    • ligand binding domain, binding specificity.
  58. orphan receptors
    receptors whos endogenous ligands are not yet identified
  59. transactivation
    effect of nuclear receptors on transcription.  Works at a distance.
  60. Who has early and late responses?
    Nuclear receptors can transcribe transcription factors, so there are often early and late responses--initial reaction then new proteins hours later.
  61. coactivators (nuclear receptor)
    • mediate transactivation, bind to ligand-receptor complex and pre-initiation complex, so can work from a distance (HUGE pile of proteins, some scaffolding)
    • have histone acetyltransferase (HAT), negative charge to make DNA bind less closely, create euchromatin
  62. corepressors
    bind unoccupied receptors or antagonist-bound to repress transcription.  Have Histone deacetylase (HDAC) activity, makes histones more positive, DNA binds more closely and creates heterochromatin.
  63. examples of passive diffusion
    simple diffusion, osmosis, facilitated diffusion (channels, solute carrier proteins IF they're working with their gradient)
  64. Definition and examples of active transport
    • use ATP (primary) or coupled transport (secondary)
    • move things against their concentration graient.  Carrier proteins, can use coupled transport.  Same way is symport, opposite is antiport.
  65. ion-transporting ATPases
    • use ATP to transport against their gradient.  
    • aka PUMPS (Na/K)
  66. Ca ATPases
    keep EXTREMELY low calcium in cell.  helped by binding proteins (calsequestrin), ER/SR, Mitochondria, SERCA, PMCA (plasma membrane calcium ATPase)
  67. F-type ATPase
    • proton pump
    • use concentration gradient to produce ATP
    • Mitochondria, chloroplasts, bacteria
  68. Inositol trisphosphate (IP3)
    ligand-gated (Ins3) calcium channel in ER. Opens when IP3 binds at cytoplasmic surface.  Comes from PIP2 cleavage (with diacylglycerol) in non-exiteable Ca signaling
  69. alternate access model
    • transporter function
    • strong interaction with substrate on one side, conformational change (reversible), exposure of substrate bidning site on opposite side of bilayer, release of substrate
  70. ball-and-chain model
    refers to ion channel with dangling protien (conformational change), can be open, closed or inactivated (when "ball" blocks opening)
  71. why don't smaller ions pass through the potassium channel?
    fully hydrated ions enter the vestibule, the channel is the perfect size to strip the water molecules off of potassium.  Sodium is too small to get stripped properly so it doesn't fit.
  72. ionophores
    • transmembrane channel or carrier, work along concentration gradient (passive).  Pore is hydrophilic and hydrated, so ions can flow through.
    • Monensin is antibiotic from streptomyces
  73. Myosin II structure
    dimer, 2 ATPase heads, 2 heavy chains, 2 pair of light chains (essential and regulatory).  Bipolar, makes up thick filament
  74. Troponin (3)
    • subunits (TN-I, TN-C binds calcium, TN-T)
    • NOT IN SMOOTH MUSCLE
    • binds tropomyosin to reveal myosin binding sites on thin filament
  75. skeletal muscle contraction mechanism
    • action potential, t-tubules (wrapped in terminal cisterna of SR), voltage-gated DHPR receptor, Ryanodine receptor (RyR), calcium from SR enters cytosol, binds troponin, tropomyosin, contraction, ATP to unhook myosin for another power stroke.  
    • SERCA returns Ca to SR
  76. Calcium-induced calcium release (CICR)
    in cardiac muscle, Ca enters the cell to stimulate RyR receptor to release the rest of Ca.  Phospholamban inhibits SERCA
  77. Smooth muscle contraction
    • no striations, ends of actin are linked to dense bodies (like Z lines).  
    • Ca binds calmodulin, activates Myosin Light Chain Kinase (MLCK), phosphorylates myosin, binds to actin.  Dephosphorylation to relax.
  78. myosin light chain kinase (MLCK)
    • smooth muscle contraction, bound by Ca-calmodulin, phosphorylates myosin
    • CaM kinase
    • Ca sensor for smooth muscle
  79. 4 ways for cells to die
    • apoptosis
    • necrosis
    • autophagy
    • cornification
  80. 3 reasons for apoptosis
    • development (fingers and toes, surplus)
    • tissue growth/regression (lactating gland)
    • remove threats (infected/damaged cells)
  81. Early signs of apoptosis
    • cells shrink, aggregate chromatin at nuclear membrane, bubbles and blebs in the plasma membrane (but intact)
    • no inflammation or immune response
  82. late signs of apoptosis
    • separate into apoptotic bodies (with intact membranes), engulfed by phagocytosis.  Nucleus fragments but other organelles intact.
    • no inflammation or immune response, just macrophages, few visible dead cells.
  83. apoptotic microscopy-based assays
    cytochrome C in the cytoplasm from mitochondrial release, external phosphatidylserine (PS) on outer leaflet of membrane (normally on inside).  "eat me"
  84. apoptotic gel electrophoresis and enzyme assay
    • gel:non-random fragmented DNA, "DNA ladder)
    • enzyme: caspase cascade
  85. tumor necrosis factor alpha, FasL
    death activator ligand, causes T-cell clearance in apoptosis
  86. extrinsic apoptosis
    external stimulus -- death ligand binds to death receptor -- caspase cascade (inactive precursor/procaspase, activated/cleaved, possible cross-talk, cleave executioner caspases -- eventually target cytoskeleton -- destruction of cell)
  87. intrinsic apoptosis
    intrinsic signal (damaged DNA) -- Bcl-2 family proteins in mitochondria -- release cytochrome C -- Apaf1 -- apoptosome -- caspase cascade (inactive precursor/procaspase, activated/cleaved, possible cross-talk, cleave executioner caspases -- eventually target cytoskeleton -- destruction of cell)
  88. Ways to keep/get Ca2+ out of cell
    • gradient is both concentration and electrochemical
    • Na/Ca exchanger (muscles and nerves) (NaCX)
    • SERCA puts it in ER
    • calsequestrin binds in ER
    • cytoplasmic buffers
    • plasma membrane Ca ATPase (PMCA)
  89. types of Ca signals
    • amplitude (size)
    • duration (time)
    • oscillation frequency (spikes or sustained)
    • spatial (localized or not)
  90. excitable cells Ca signaling
    • nerve and muscle
    • usually voltage-sensitive calcium channels (can be ligand or receptor like nicotinic ACH or NMDA)
    • synapse: membrane depolarization, voltage Ca channel opens, initiates release of synaptic vesicles (synaptotagmin)
    • Cardiac muscle cell:Ca into cell, triggers RyR receptor, Ca release, troponin, Ca in mitochondria to stimulate ATP production.
  91. non-excitable cells Ca signaling (inositol phospholipid)
    G-protein or tyrosine kinase receptor -- phospholipase C (PLC) -- cleaves PIP2 in plasma membrane -- diacylglycerol (activates protein kinase C) and inositol trisphosphate (IP3) (releases Ca from ER)
  92. non-excitable cells Ca signaling (store operated Ca channels)
    when RyR lets Ca out, would be too short, needs help, so Store Operated Calcium Channels (SOCs) are used.  When IP3 empties ER, STIM1 senses that it is empty, communicates with Orai1 (a capacitative calcium entry channel in membrane), open to allow extracellular in.
  93. phospholipase C
    cleaves PIP2 in plasma membrane to make diacylglycerol and IP3 in non-excitable Ca signaling
  94. protein kinase C
    activated by diacylglycerol in non-excitable Ca signaling
  95. STIM1
    ER Ca2+ sensor, notices when ER is empty, contacts Orai1 to let extracellular Ca into the cell in store-operated calcium channel signaling, prolonging contraction.
  96. Orai1
    capacitative calium entry channel, opened by a signal from STIM1 that the ER is empty of Ca.  Prolongs time of contraction in store-operated calcium channel activation.
  97. synaptotagmin
    calcium binding protein in synaptic vesicles
  98. calmodulin
    • calcium binding protein (ubiquitous)
    • Ca/calmodulin-dependent protein kinase II (CaM-kinaseII).  Frequency detector for molecular memory
  99. constituitive exocytosis and example
    • container fuses with no need for further signals
    • mammary alveoli
    • biopharming (goats secrete glycosylated proteins in milk)
  100. regulated exocytosis
    • will only fuse with a further signal
    • sperm/egg fusion (contact-dependent), insulin (endocrine, pancreatic beta cell brings vesicle full of glc receptors), neuronal synapse (paracrine)
  101. SNARE proteins
    • bilayer fusion
    • amphipathic membrane proteins, form coiled-coil structure, 4 helices,  
    • Synaptobrevin (v-snare), synaptotaxin (t-snare), SNAP-25 (2 helices)
    • targeted by clostridium botulinum
  102. NSF
    • ATPase chaparone that helps achieve conformation
    • UNFOLDS proteins, detangles SNARES for recycling
  103. Specialized lysosome situation
    • Some lysosomes are meant to secrete: sperm acrosome, melanosome, granules of cytotoxic T lymphocytes
    • ALL lysosomes can fuse with plasma membrane if needed, when lots of membrane is needed as in injury
  104. 2 roles of extracellular matrix
    signaling and structure
  105. fibrous proteins in ECM (3)
    • collagens (fibrillar, fibril-associated, network-forming and anchoring)
    • elastin (recoil)
    • fibronectin (organize ECM with integrins, like laminin)
  106. four types of collagen
    • fibrillar (I, II): long and rope-like.  Most common.  Scar, strength, hands.  
    • fibril-associated (IX, XII): organize fibrils, link to each other and ECM
    • network-forming (IV): basement membrane.  Flexible
    • anchoring (VII): anchor basement membrane to underlying CT
  107. 2 molecule classes in ECM
    glycosaminoglycans and fibrous proteins
  108. glycosaminoglycans (GAGs) (3)
    • Hyaluronic acid: HUGE, simple, attracts water. No core protein.  Synovium, gubernaculum, shar pei
    • proteoglycans: core-protein-linked.  form sieves like glomerular filtration barrier. signaling.  Major one is aggrecan
    • Aggrecan: proteoglycan of articular cartilage
  109. laminin
    organizer of basement membranes (like fibronectin but in the basement)
  110. integrins
    • transmembrane protiens, link to cytoskeleton (talin).
    • Velcro.
    • Can activate inside-out
    • call up focal adhesion kinase in cell motility
  111. anchoring junctions
    transmit stresses and connect cells.  cell-cell adhesions (adherens junctions and desmosomes) and cell-matrix adhesions (actin-linked cell-matrix adhesions and hemidesmosomes)
  112. types of jucntions that allow cells to form an epithelium
    anchoring jucntions and occluding/tight junctions
  113. adherens junction
    • cell-cell, links to actin, uses cadherin proteins.  coordinate motility, adhesion belt.
    • 2nd most apical
  114. desmosomes
    • cell-cell, link to intermediate filaments, uses cadherin proteins.  strong attachments like muscle to tendon.  Pemphigus.
    • least apical
  115. actin-linked-cell-matrix adhesion
    cell-matrix, attaches to actin, basal on cell, integrins are protein.
  116. hemidesmosomes
    cell-matrix, uses integrins, basal on cell, attaches to intermediate filaments
  117. cadherins
    • calcium-dependent adhesion proteins (adherens junctions and desmosomes)
    • velcro (like integrins)
    • bind with catenins to EXACT match on other cells, specificity (homophilic)
    • control selective assortment on cells--decided neural crest cells should leave neural tube, or epithelia to mesenchymal.
  118. epithelial-mesenchymal transition
    • TWIST tells epithelial cells to stop expressing cadherins, they act mesenchymal and drift in wound healing or development.  
    • beta-catenin is either an adhesion protein (epithelia) or a transcription factor (mesenchymal)
  119. beta-catenin
    • either an adhesion protein (epithelia) or a transcription factor (mesenchymal)
    • TWIST or SNAIL
  120. tight/occluding junctions
    • most apical in cell
    • form a seal between adjacent cells so nobody goes between
    • paracellular transport is when things are allowed between
    • segregates apical and basal in cell
    • claudins (strucutre) and occludins (ion permeability)
  121. focal adhesion kinase (FAK)
    when cells are moving they have steps, one is focal adhesions for traction.  Integrins recruit focal adhesion kinase to be the boss of motility.  helps in dissembling attachments at the rear.
  122. type I insulin dependent diabetes mellitus
    failure to produce insulin
  123. type II non-insulin dependent diabetes mellitus
    insulin resistence, obesity a factor
  124. GLUT2 vs GLUT4
    • GLUT4 promotes glucose uptake in adipose (triglycerides) and muscle (glycogen)
    • GLUT2 promotes uptake in liver (breakdown nothing, make macromolecules)
    • insulin signaling brings them to the surface in vesicles (SNARE)
  125. insulin mechanism
    insulin (IS A TYROSINE KINASE, preformed dimer) -- receptor -- transautophosphorylation -- phosphorylates IRS-1 -- PI3 binds, PI-3 kinase -- PIP2 -- PIP3 plekstrin homology domain -- bind Akt, PDK1 -- PDKI + mTORC2 activate Akt -- phosphorylates targets -- GLUT4 vesicles to membrane.
  126. what kind of receptor is insulin?
    tyrosine kinase, preformed dimer
  127. what kind of receptor is glucocorticoid?
    nuclear.

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