Evolutionary pharmacology at the neuromuscular junction W. Rose

Applied pharmacology advocacy.britannica.com/blog/advocacy/wp- content/uploads/poison-frog.jpg y-crawlies-land/cone-snail

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 presynaptic ACh release

Applied pharmacology

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

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

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

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

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