Evolutionary pharmacology at the neuromuscular junction

W. Rose

Applied pharmacology

www.itsnature.org/ground/creepy-crawlies-land/scorpion

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www.itsnature.org/ground/creepy-crawlies-land/cone-snail

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

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