Cell physiology1

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Cell physiology1

  1. 1. In the name of GOD
  2. 2. Physiology of the cell by H. Khorrami Ph.D. http://khorrami1962.spaces.live.com khorrami4@yahoo.com
  3. 3. Contents: • Plasma membrane • Some cellular organells • Transport across membrane • Membrane potential: resting & action potential • Refractory period • Chronaxie, rheobase, length constant, • Synapses, electrical & chemical • EPSP, IPSP • Adaptation, plasticity, post tetanus potentiation, long term potentiation • Lateral inhibition, synaptic fatigue, • Receptive field • Summation: temporal, spacial • Signal transduction • G-proteins • Apoptosis & necrosis • Muscle fiber, neuromuscular junction, contraction, twitch, motor unit, • Isometric & isotonic contraction • Muscle metabolism, fatigue
  4. 4. Cell membrane • Two layer phospholipids ( 45% of weight) • 2 × 1.7 + 0.1 nm • Proteins ( 55% of weight) • + 2 × 2nm • Structural • Integral • Channel • Pump • Enzymes • Receptors • Orphan • Non-orphan • Carbohydrates
  5. 5. Properties of membranes
  6. 6. Fluid mosaic model
  7. 7. Lipids
  8. 8. Phospholipids
  9. 9. Membrane lipids
  10. 10. Fatty acids
  11. 11. Phospholipids' head groups
  12. 12. Fatty acid tails
  13. 13. Glycolipids
  14. 14. Cholesterol
  15. 15. Membrane asymmetry
  16. 16. Organelle lipids
  17. 17. Lateral organization
  18. 18. Membrane curvature
  19. 19. Transport of lipids
  20. 20. Lipid synthesis
  21. 21. Non-vesicular lipid transport
  22. 22. Movements in membrane • Phlip-phlap • Rotation • Lateral diffusion ( 107 per second) • Flexion
  23. 23. Functions of carbohydrates • Negative surface charge • Attachment of cells together • As receptor • Immune recognition
  24. 24. Lysosomes Lysosomal storage Enzyme involved Problem disease(LSD) Pompe α-glucosidase Glycogen in hepatocytes MPS Glycosaminoglycans Tay-Sachs Hexosaminidase A Gangliosid Hypoxanthine-guanine- Gout Uric acid phosphoribosyl-tansferase Leprosy, silicosis,
  25. 25. Na: 15 Na: 145 Cl: 4 Cl: 104 K: 150 K: 5 Mg Ca: 10-3 - PO4+ Hco3 AA Glucose Fat Po2 Pco2 PH: 7.40 Protein PH: 7.00
  26. 26. Osmosis • Osmolarity • Osmolality • Isotonic, hypotonic & hypertonic
  27. 27. Osmosis
  28. 28. Osmotic pressure • Based on decrease in freezing point • A one molar solute -1.86⁰ C • Plasma… -0.52 • 280mmol • pv=nRT, p×1=1×62.63×310 • A one molar solute 19200mmHg • Osmotic pressure of plasma? • 5600mmHg
  29. 29. Could a hyperosmolar solution be isotonic? • Yes • Because tonicity depend on permeability of the membrane
  30. 30. Membrane transport • Diffusion • Facilitated diffusion • Active transport
  31. 31. Simple & facilitated diffusion Simple diffusion Facilitated diffusion No saturation Saturation(Vmax) Fast Low velocity Chemical gradient Carrier protein Linear correlation Non-linear correlation Competition
  32. 32. Diffusion • Fick’s law: • J = - DA(dc/dx)
  33. 33. Secondary active transport • Symport – Intestine – Kidney – Glucose & AA • Antiport – Heart – Rbc – Calcium, H+, HCO3, Cl- …
  34. 34. Ion Channels • Leak channels • Voltage-gated channels • Ligand-gated channels – Intracellular – Extracellular • Mechanically-gated channels
  35. 35. Sodium channel
  36. 36. Glucose transporters transporter tissue function insulin stimulation • Facilitative glucose transporters • GT-1 BBB, Rbc, fibroblast glu uptake + • GT-2 liver,β cell, intestine low-affinity - • GT-3 brain, fibroblast glu uptake ? • GT-4 fat, skl. muscle, heart glu uptake +++ • GT-5 small intestine, sperm fruc. transp. ? • Active glucose transporters • SGT-1 intestine, kidney intes. renal reabs -
  37. 37. Resting potential
  38. 38. Resting potential
  39. 39. Action potential
  40. 40. Na-voltage gated channel
  41. 41. Action potential
  42. 42. Threshold
  43. 43. Na channel
  44. 44. Review
  45. 45. Falling phase
  46. 46. Undershoot
  47. 47. Refractory period
  48. 48. Resting state
  49. 49. Depolarising phase
  50. 50. Repolarising phase
  51. 51. Undershoot
  52. 52. Blocking the channel
  53. 53. Potassium channels in AP • Delayed rectifier K ch – In repolarization • Early K ch – Reduce the velocity of depolarization • Calcium-activated K ch – Preventing repetitive stimulation
  54. 54. Action potential equations • Nernst: – Ek= -RT/ZF Ln [K]i/ [K]o • Goldman-Hodgkin: – Ek= -RT/ZF Ln P[K]i+ P[Na]i+ P[cl]o/ P[K]o+ P[Na]o+ P[cl]i
  55. 55. Comparison of synapses Electrical Chemical Bidirectional Unidirectional No delay Delay (1-2ms) Fast Slow
  56. 56. Century 21st
  57. 57. Gap junction
  58. 58. Electrical synapse
  59. 59. Gap junction
  60. 60. K channel
  61. 61. Nernst equation
  62. 62. Goldman equation
  63. 63. Functions of the electrical transmission 1.Electrical synapses are more reliable, less likely to fail. 2.Greater speed –important in rapid reflexes involving escape reactions. 3.The synchronization of electrical activity of groups of cells. 4.Intracellular transfer of molecules such as Ca, ATP and cAMP. 5.The activity of gap junctions between cells in the retina can be modulated by dopamine. Thus the gap junctions can be dynamic components of neuronal circuits. 6. Mutations in the genes encoding gap junction proteins cause diseases: •Peripheral neuropathy –Charcot-Marie-Tooth disease •Abnormal cardiac development •Congenital deafness Charcot-Marie-Tooth disease –inherited peripheral neuropathy -degeneration of peripheral nerves -Foot deformities, muscle wasting, distal sensory loss, decreased tendon reflexes Gap junction is necessary for radial migration in the neocortex
  64. 64. Chemical synapse
  65. 65. Chemical synapse • neurotransmitter • Depolarization of the presynaptic nerve terminal • Triggers the release of molecules Interact with receptors on the postsynaptic neuron • Excitation or inhibition of the postsynaptic neuron.
  66. 66. Neurotransmitters: Definition: • Synthesized by presynaptic neuron • Released by stimulation • Microapplication of NT. Mimic the presyn. stimulation • Presynaptic & microappl. Stim. Must be blocked by pharmacologic agent • High affinity uptake mechanism for the substance in synaptic terminal release of NT, synapsin 6/9/2010 91
  67. 67. Neurotransmitters • Small molecules • Neuropeptides  Opioid peptides  Ach Leucine enkephalin  Biogenic amines Methionine enkephaline b - endorphin Dopamine Dynorphins Norepinephrine  Pituitary peptide Epinephrine Oxytocin 5-HT Vasopressin ACTH Histamine TSH  Amino acids  Gastrointestinal peptides Aspartate CCK GABA Sub-P Glutamate Neurotensin Glycine Homocystein Gastrin Taurine Insulin  Nucleotides Glucagon Adenosine Somatostatin ATP  Others  Retrograde gases Angiotensin Nitric oxide Bradykinin Carbon monoxide Neuropeptide Y 6/9/2010 92
  68. 68. Receptors of NTs • Ionotropic: • Metabotropic: ligand gating i.e. nicotinic work by second receptor (inhibited by messenger curare) (G protein) 6/9/2010 93
  69. 69. Neuropharmacology of some receptors Neurotransmitter Receptor subtype Agonist Antagonist Acetylcholine(Ach) Nicotinic receptor Nicotine Curare Muscarinic Muscarine Atropine receptor Glutamate AMPA AMPA CNQX NMDA NMDA AP5 GABA GABAA Muscimol Bicuculine GABAB Baclofen Phaclofen
  70. 70. Acetylcholine
  71. 71. Catecholamines
  72. 72. Serotonin synthesis
  73. 73. Glutamate receptor • Non-NMDA; • NMDA; • kainate receptor & • Gating channel is • AMPA permeable to Na, K, Mg – permeability  to Na & & Ca2+ K • Magnesium block – Excitatory • Act on this receptor – Act on this receptor at when depolarized rest (voltage-dependent) N-Methyl-D-Aspartate , α-amino-3-OH-5-methyl-4-isoxasole propionate 6/9/2010 98
  74. 74. Glutamate receptors
  75. 75. Calcium can trigger • Enzymatic activity • Opening of a variety of channels • Gene expression • Cell death • Long-term memory
  76. 76. Glutamate receptors • Activation of AMPA • Na+ inward & K+ outward • Depolarization • Pop out of Mg2+ from the pore of NMDA
  77. 77. Voltage-dependent NMDA
  78. 78. Excitotoxicity • High demand of brain cells to oxygen & glucose • Cardiac arrest, stroke, ….. • Limits of ATP • Depolarizing the membrane • Calcium leak into cells • Glutamate release • Depolarization • More calcium • …………… • Cell death
  79. 79. TTX
  80. 80. Length constant
  81. 81. Components of a second messenger cascade
  82. 82. Nicotinic receptor
  83. 83. Acetylcholine
  84. 84. Acetylcholine receptors Name Location Blocked by Agonists Muscarinic End of postgang. Atropine Metacholine parasym Carbachol Betanechol Pilocarpine Nicotinic Autonomic ganglia Scopolamine Nicotine Adrenal medulla Hexamethonium N-M junction Tubocurarine
  85. 85. Ach (muscarinic receptor)
  86. 86. Norepinephrine
  87. 87. Inhibitory neurotransmitter
  88. 88. Cell-to-cell communication by extracellular signaling usually involves six steps • Synthesis of the signaling molecule by the signaling cell • Release of the signaling molecule by the signaling cell • Transport of the signal to the target cell • Detection of the signal by a specific receptor protein • A change in cellular metabolism, function, or development triggered by the receptor-signal complex • Removal of the signal, which usually terminates the cellular response
  89. 89. Signaling molecules operate over various distances in animals
  90. 90. Cell-surface receptors
  91. 91. Signal transduction steps • Ligand binds to the receptor • Dissociation of a subunit from b & g • Exchanging GDP with GTP • Moving a subunit • Activation of adenylyl cyclase or GC • Second messenger( cAMP) • Binding cAMPs to R subunit of Protein kinase • Dissociation & activation of C subunit • Phosphorylation of target protein • Cell response
  92. 92. Cell-surface receptors
  93. 93. Second messengers
  94. 94. Other conserved proteins function in signal transduction: GTPase switch proteins
  95. 95. Other conserved proteins function in signal transduction: protein kinases
  96. 96. Other conserved proteins function in signal transduction: adapter proteins
  97. 97. Common signaling pathways are initiated by different receptors in a class
  98. 98. hormone signal outside GPCR plasma The a subunit of membrane a G-protein (Ga) a g g  a cytosol binds GTP, & can AC GDP b b GTP hydrolyze it to GDP + Pi. GTP GDP ATP cAMP + PPi a & g subunits have covalently attached lipid anchors that bind a G-protein to the plasma membrane cytosolic surface. Adenylate Cyclase (AC) is a transmembrane protein, with cytosolic domains forming the catalytic site.
  99. 99. hormone signal outside GPCR plasma membrane a g g  a cytosol AC GDP b b GTP GTP GDP ATP cAMP + PPi The sequence of events by which a hormone activates cAMP signaling: 1. Initially Ga has bound GDP, and a, b, & g subunits are complexed together. Gb,g, the complex of b & g subunits, inhibits Ga.
  100. 100. hormone signal outside GPCR plasma membrane a g g  a cytosol AC GDP b b GTP GTP GDP ATP cAMP + PPi 2. Hormone binding, usually to an extracellular domain of a 7-helix receptor (GPCR), causes a conformational change in the receptor that is transmitted to a G-protein on the cytosolic side of the membrane. The nucleotide-binding site on Ga becomes more accessible to the cytosol, where [GTP] > [GDP]. Ga releases GDP & binds GTP (GDP-GTP exchange).
  101. 101. hormone signal outside GPCR plasma membrane a g g  a cytosol AC GDP b b GTP GTP GDP ATP cAMP + PPi 3. Substitution of GTP for GDP causes another conformational change in Ga. Ga-GTP dissociates from the inhibitory bg complex & can now bind to and activate Adenylate Cyclase.
  102. 102. Identification and purification of cell-surface receptors Hormone receptors are detected by binding assays
  103. 103. KD values for cell-surface hormone receptors approximate the concentration of circulating hormones
  104. 104. G protein-coupled receptors and their effectors • Many different mammalian cell-surface receptors are coupled to a trimeric signal-transducing G protein • Ligand binding activates the receptor, which activates the G protein, which activates an effector enzyme to generate an intracellular second messenger • All G protein-coupled receptors (GPCRs) contain 7 membrane-spanning regions with their N-terminus on the exoplasmic face and C-terminus on the cytosolic face • GPCRs are involved in a range of signaling pathways, including light detection, odorant detection, and detection of certain hormones and neurotransmitters
  105. 105. G protein-coupled receptors
  106. 106. The structure of adenylyl cyclase
  107. 107. Trimeric Gs protein links b-adrenergic receptors and adenylyl cyclase
  108. 108. Some bacterial toxins irreversibly modify G proteins
  109. 109. Adenylyl cyclase is stimulated and inhibited by different receptor- ligand complexes
  110. 110. Types of G-proteins • Ras (growth factor signal cascades) • Rab (membrane vesicle targeting and fusion) • ARF (formation of vesicle coatomer coats) • Ran (transport of proteins into & out of the nucleus) • Rho (regulation of actin cytoskeleton)
  111. 111. Ras cycles between active and inactive forms
  112. 112. Receptor tyrosine kinases and Ras • Receptor tyrosine kinases recognize soluble or membrane bound peptide/protein hormones that act as growth factors • Binding of the ligand stimulates the receptor’s tyrosine kinase activity, which subsequently stimulates a signal- transduction cascade leading to changes in cell physiology and/or patterns of gene expression • RTK pathways are involved in regulation of cell proliferation and differentiation, promotion of cell survival, and modulation of cellular metabolism • RTKs transmit a hormone signal to Ras, a GTPase switch protein that passes on the signal on to downstream components
  113. 113. Ligand binding leads to autophosphorylation of RTKs
  114. 114. An adapter protein and GEF link most activated RTKs to Ras
  115. 115. Opening of ryanodine receptors releases Ca2+ stores in muscle and nerve cells
  116. 116. Signal transduction

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