Evolutionary pharmacology at the neuromuscular junction W. Rose
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Transcript of Evolutionary pharmacology at the neuromuscular junction W. Rose
Evolutionary pharmacology at the neuromuscular junction
W. Rose
Applied pharmacology
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Applied pharmacology of action potentials and NMJ
Scorpion toxin: holds open voltage-dependent Na channelsCharybdotoxin (scorpion): blocks Ca-activated volt.-dep. K channelsTetrodotoxin (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 releaseMohave 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: GABAB agonist, opens K channels
Nucleus
Actionpotential (AP)
Myelinated axonof motor neuron
Axon terminal ofneuromuscular junction
Sarcolemma ofthe muscle fiber
Ca2+Ca2+
Axon terminalof motor neuron
Synaptic vesiclecontaining ACh
MitochondrionSynapticcleft
Fusing synaptic vesicles
1 Action potential arrives ataxon terminal of motor neuron.
2 Voltage-gated Ca2+ channels open and Ca2+ enters the axon terminal.
Marieb & Hoehn 8th ed. Figure 9.8
Marieb & Hoehn 8th ed. Figure 9.8
Nucleus
Actionpotential (AP)
Myelinated axonof motor neuron
Axon terminal ofneuromuscular junction
Sarcolemma ofthe muscle fiber
Ca2+Ca2+
Axon terminalof motor neuron
Synaptic vesiclecontaining AChMitochondrionSynapticcleft
Junctionalfolds ofsarcolemma
Fusing synaptic vesicles
ACh
Sarcoplasm ofmuscle fiber
Postsynaptic membraneion channel opens;ions pass.
Na+ K+
Ach–
Na+
K+
Degraded ACh
Acetyl-cholinesterase
Postsynaptic membraneion channel closed;ions cannot pass.
1 Action potential arrives ataxon terminal of motor neuron.
2 Voltage-gated Ca2+ channels open and Ca2+ enters the axon terminal.
3 Ca2+ entry causes some synaptic vesicles to release their contents (acetylcholine)by exocytosis.
4 Acetylcholine, aneurotransmitter, diffuses across the synaptic cleft and binds to receptors in the sarcolemma.
5 ACh binding opens ionchannels that allow simultaneous passage of Na+ into the musclefiber and K+ out of the muscle fiber.
6 ACh effects are terminated by its enzymatic breakdown in the synaptic cleft by acetylcholinesterase.
Marieb & Hoehn 8th ed. Figure 9.10
Na+ channelsclose, K+ channelsopen
K+ channelsclose
Repolarizationdue to K+ exit
Threshold
Na+
channelsopen
Depolarizationdue to Na+ entry
Marieb & Hoehn 8th ed. Figure 9.9
Na+
Na+
Open Na+
Channel
Closed Na+
Channel
Closed K+
Channel
Open K+
Channel
Action potential++++++
+++++
+
Axon terminal
Synapticcleft
ACh
ACh
Sarcoplasm of muscle fiber
K+
2 Generation and propagation ofthe action potential (AP)
3 Repolarization
1 Local depolarization: generation of the end plate potential on the sarcolemma
K+
K+Na+
K+Na+
Wave ofde
po
lari
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n