neuron_drug_targets_post.ppt

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  • neuron_drug_targets_post.ppt

    1. 1. VOODOO PHARMACOLOGY Basic Neuronal Transmission or How These Animals Eat
    2. 2. Overview of Nervous System Organization
    3. 3. Neuron Structure
    4. 5. The central nervous system
    5. 6. The Human Brain
    6. 8. 2.25 Lateral view of the exterior cerebral cortex
    7. 9. Neurotransmission
    8. 10. Neuronal Transmission Neurotransmitter stimulate next neuron Neurons synapse with other neurons Wave of electrical current passes down the axon Current triggers release of neurotransmitter
    9. 11. Distribution of ions inside and outside a neuron
    10. 12. Membrane potential recording from a squid axon
    11. 13. Ion Channels Create Ion Gradients
    12. 14. Stages of the action potential
    13. 15. 1. Sodium channel opens
    14. 16. 2. Potassium channel opens
    15. 17. Wave of depolarization moves down the axon Another animation: www.blackwellscience.com/matthews/ animate.html
    16. 18. Overview of Chemical Transmission
    17. 19. Synaptic transmission: simple version
    18. 20. Release of Neurotransmitter
    19. 21. Vesicular Release of Simple Neurotransmitters
    20. 22. Proteins and Vesicular Release
    21. 23. Vesicular Proteins involved in Release
    22. 24. Release of Peptide Neurotransmitters
    23. 25. Neurotransmitter inactivation
    24. 26. Terminal and somatodendritic autoreceptors
    25. 27. Postsynaptic Receptors
    26. 28. Postsynaptic Acetylcholine Receptor
    27. 29. Summation of local potentials
    28. 30. Molecules are Targets not Anatomic Units Na K Receptor Channels Vesicle proteins Metabolizing enzymes
    29. 31. Channels as Targets <ul><li>Sodium Channel </li></ul><ul><ul><li>Block: stop action potential </li></ul></ul><ul><ul><li>Prevent inactivation: stimulation then failure </li></ul></ul><ul><li>Potassium Channel </li></ul><ul><ul><li>Block: No repolarization: repetitive activity </li></ul></ul><ul><ul><li>Open: Neuron can’t be activated </li></ul></ul>Na K
    30. 33. Sodium Channel Toxins <ul><li>Block: </li></ul><ul><ul><li>Tetrodotoxin (Puffer fish) </li></ul></ul><ul><ul><li> Conotoxins (Cone mollusks) </li></ul></ul><ul><li>Activate/prevent inactivation </li></ul><ul><ul><li>Saxitoxin- Dinoflagellates </li></ul></ul><ul><ul><li> and  Scorpion Toxins </li></ul></ul><ul><ul><li>Batrachotoxin: poison dart frogs </li></ul></ul>
    31. 34. Potassium Channel Toxins <ul><li>Block </li></ul><ul><ul><li>Apamin (Honey bee) </li></ul></ul><ul><ul><li>Dendrotoxin (Green mamba) </li></ul></ul><ul><ul><li>Charybdotoxin (Scorpion ) </li></ul></ul>
    32. 35. Conotoxins: multipurpose toxins <ul><li>Peptide neurotoxins </li></ul><ul><ul><li>Calcium channels specific for muscles </li></ul></ul><ul><ul><li>Sodium channels </li></ul></ul><ul><ul><li>Potassium channels </li></ul></ul>
    33. 36. Poison Dart Frogs <ul><li>Toxins in skin discourage predation </li></ul><ul><li>Toxins from food (ingested insects?) </li></ul><ul><li>Combination of ion channel toxins </li></ul><ul><ul><li>Batrachotoxins </li></ul></ul>
    34. 37. Terminals as Targets <ul><li>Activate release </li></ul><ul><li>Black widow spider </li></ul><ul><li>Inhibit release </li></ul><ul><li>Botulinum toxin </li></ul>Terminals
    35. 38. Botulinum Toxin: Medicine or Weapon of War? <ul><li>Bacterial toxin (Clostridium botulinum) </li></ul><ul><li>Binds Ach terminal </li></ul><ul><li>Zinc proteases- there are 7 toxin isoforms (A-G) </li></ul><ul><li>Cleave proteins involved in vesicle fusion with membrane </li></ul><ul><ul><li>Synaptobrevin </li></ul></ul><ul><ul><li>SNAP25 </li></ul></ul><ul><ul><li>syntaxin </li></ul></ul><ul><li>Prevents neurotransmitter release </li></ul>
    36. 39. Bo-Tox (Botulinum Toxin A <ul><li>Injected locally: paralyzes neuromuscular junction </li></ul><ul><li>Use originally for facial spasm </li></ul><ul><li>Used widely in cosmetic surgery </li></ul><ul><li>Is it a viable weapon????? </li></ul>
    37. 40. Latrotoxin (Black Widow Spider Venom) Binds Neurexin: triggers vesicle fusion Neurexin Latrophilin Calcium Calcium
    38. 41. Receptors as Targets <ul><li>Antagonists : prevent receptor activation </li></ul><ul><li>Agonists : stimulate then inactivate </li></ul><ul><li>Acetylcholinesterase inhibitors : prevent degradation </li></ul>Receptor
    39. 42. Acetylcholine Receptor Toxins <ul><li>Antagonists </li></ul><ul><li>Cobra toxins </li></ul><ul><li>Alpha bungarotoxin (Krait) </li></ul><ul><li>Alpha neurotoxin (mamba) </li></ul><ul><li>Agonists </li></ul><ul><li>Nicotine </li></ul><ul><li>ACH inhibitors </li></ul><ul><li>Mamba toxins: fasiculins </li></ul>
    40. 43. Summary of Toxin Sites Na K Tetrodotoxin Dendrotoxin Latrotoxin (increases) Botulinum (blocks) Bungarotoxin Alpha neurotoxin
    41. 44. Mechanisms by which drugs can alter synaptic transmission
    42. 45. Voodoo Pharmacology: Zombi <ul><li>Give tetrodoxin: paralyze and decrease oxygen requirement </li></ul><ul><li>Bury until limited brain damage has occurred </li></ul><ul><li>Dig up and he is yours to control </li></ul>

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