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