neuron_drug_targets_post.ppt

VOODOO PHARMACOLOGY

Basic Neuronal Transmission or How These Animals Eat

Overview of Nervous System Organization

Neuron Structure

The central nervous system

The Human Brain

2.25 Lateral view of the exterior cerebral cortex

Neurotransmission

Neurotransmitter stimulatenext neuron

Neuronal Transmission

Neurons synapsewith other neurons

Wave of electrical current passesdown the axon

Current triggers release of neurotransmitter

Distribution of ions inside and outside a neuron

Membrane potential recording from a squid axon

Ion Channels Create Ion Gradients

Stages of the action potential

1. Sodium channel opens

2. Potassium channel opens

Wave of depolarization moves down the axon

Another animation: www.blackwellscience.com/matthews/

animate.html

Overview of Chemical Transmission

Synaptic transmission: simple version

Release of Neurotransmitter

Vesicular Release of Simple Neurotransmitters

Proteins and Vesicular Release

Vesicular Proteins involved in Release

Release of Peptide Neurotransmitters

Neurotransmitter inactivation

Terminal and somatodendritic autoreceptors

Postsynaptic Receptors

Postsynaptic Acetylcholine Receptor

Summation of local potentials

NaK

Receptor

Molecules are Targets not Anatomic Units

Channels

Vesicle proteinsMetabolizingenzymes

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

Sodium Channel Toxins

• Block:– Tetrodotoxin (Puffer fish) Conotoxins (Cone mollusks)

• Activate/prevent inactivation– Saxitoxin- Dinoflagellates and Scorpion Toxins– Batrachotoxin: poison dart frogs

Potassium Channel Toxins

• Block– Apamin (Honey bee)– Dendrotoxin (Green mamba)– Charybdotoxin (Scorpion)

Conotoxins: multipurpose toxins

• Peptide neurotoxins– Calcium channels

specific for muscles

– Sodium channels

– Potassium channels

Poison Dart Frogs

• Toxins in skin discourage predation

• Toxins from food (ingested insects?)

• Combination of ion channel toxins– Batrachotoxins

Terminals

Terminals as Targets

• Activate release• Black widow spider• Inhibit release• Botulinum toxin

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

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?????

Latrotoxin (Black Widow Spider Venom)

Calcium

Binds Neurexin: triggers vesicle fusion

Neurexin

LatrophilinCalcium

Receptors as Targets

• Antagonists: prevent receptor activation

• Agonists: stimulate then inactivate

• Acetylcholinesterase inhibitors: prevent degradation

Receptor

Acetylcholine Receptor Toxins

• Antagonists• Cobra toxins• Alpha bungarotoxin (Krait)• Alpha neurotoxin (mamba)• Agonists• Nicotine• ACH inhibitors• Mamba toxins: fasiculins

Na

K

Summary of Toxin Sites

Tetrodotoxin

Dendrotoxin

Latrotoxin (increases)

Botulinum (blocks)BungarotoxinAlpha neurotoxin

Mechanisms by which drugs can alter synaptic transmission

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