Evolutionary pharmacology at the neuromuscular junction W. Rose

1. Evolutionary pharmacology at the neuromuscular junction W. Rose

2. Applied pharmacology www.itsnature.org/ground/creepy-crawlies-land/scorpion advocacy.britannica.com/blog/advocacy/wp-content/uploads/poison-frog.jpg www.itsnature.org/ground/creepy-crawlies-land/cone-snail

3. Applied pharmacology of action potentials and NMJ Scorpion  toxin: holds open voltage-dependent Na channels Charybdotoxin (scorpion): blocks Ca-activated volt.-dep. K channels Tetrodotoxin (pufferfish, frogs): blocks voltage-dep. Na channels -cobratoxin (cobra): blocks nicotinic ACh receptor -conotoxin (cone snail): blocks N-type Ca channel in axon terminals -latrotoxin (black widow spider): Ca influx to nerve terminal and massive neurotransmitter release Mohave toxin (Mohave rattlesnake): blocks presynapticACh release

4. Applied pharmacology

5. Applied pharmacology of action potentials and NMJ Organophosphates (insecticides): acetylcholinesterase inhibition Botulinum toxin (Botox): blocks presynapticACh release by interfering with SNARE proteins, which facilitate vesicle-membrane fusion Baclofen: GABAB agonist, opens K channels

6. Myelinated axon of motor neuron Action potential (AP) Axon terminal of neuromuscular junction Nucleus Sarcolemma of the muscle fiber 1 Action potential arrives at axon terminal of motor neuron. Ca2+ Synaptic vesicle containing ACh Ca2+ 2 Voltage-gated Ca2+ channels open and Ca2+ enters the axon terminal. Mitochondrion Synaptic cleft Axon terminal of motor neuron Fusing synaptic vesicles Marieb & Hoehn 8th ed. Figure 9.8 Figure 9.8

7. Myelinated axon of motor neuron Action potential (AP) Axon terminal of neuromuscular junction Nucleus Sarcolemma of the muscle fiber 1 Action potential arrives at axon terminal of motor neuron. Ca2+ Synaptic vesicle containing ACh Ca2+ 2 Voltage-gated Ca2+ channels open and Ca2+ enters the axon terminal. Mitochondrion Synaptic cleft Axon terminal of motor neuron 3 Ca2+ entry causes some synaptic vesicles to release their contents (acetylcholine) by exocytosis. Fusing synaptic vesicles Junctional folds of sarcolemma ACh 4 Acetylcholine, a neurotransmitter, diffuses across the synaptic cleft and binds to receptors in the sarcolemma. Sarcoplasm of muscle fiber Postsynaptic membrane ion channel opens; ions pass. 5 ACh binding opens ion channels that allow simultaneous passage of Na+ into the muscle fiber and K+ out of the muscle fiber. K+ Na+ Degraded ACh 6 ACh effects are terminated by its enzymatic breakdown in the synaptic cleft by acetylcholinesterase. Ach– Postsynaptic membrane ion channel closed; ions cannot pass. Na+ Acetyl- cholinesterase K+ Marieb & Hoehn 8th ed. Figure 9.8

8. Na+ channels close, K+ channels open Depolarization due to Na+ entry Repolarization due to K+ exit Na+ channels open Threshold K+ channels close Marieb & Hoehn 8th ed. Figure 9.10

9. Axon terminal Open Na+ Channel Closed K+ Channel Synaptic cleft Na+ ACh K+ Na+ K+ + + + + ACh + + + + + + Action potential n + + o i Na+ K+ t a 2 Generation and propagation of the action potential (AP) z i r a l o p e d f o e v Closed Na+ Channel Open K+ Channel a W 1 Local depolarization: generation of the end plate potential on the sarcolemma Na+ K+ 3 Repolarization Sarcoplasm of muscle fiber Marieb & Hoehn 8th ed. Figure 9.9