Lecture 5. Nicotinic Receptors of the Neuromuscular Junction & Autonomic Ganglia Flashcards
What competitively blocks reuptake of choline?
Hemicholinium 3
What is reuptake of choline dependent on?
Na⁺
What synthesises ACh from precursors choline and Acetyl Co-A from mitochondria?
Choline acetyltransferase (ChAT)
What selectively inhibits ChAT?
Nothing, recent evidence suggests that it may be inhibited by amyloid proteins seen in Alzheimer’s disease
What inhibits uptake and storage of ACh in synaptic vesicles?
Vesamicol
What does tetrodotoxin (TTX) block?
Voltage-gated Na⁺ channels (no action potential - no release)
What blocks P/Q & N-type voltage-gated Ca²⁺ channels?
Various toxins eg conatoxins (no Ca²⁺ influx - no release)
What does botulinum toxin block?
Vesicle fusion - no release
What do dendrotoxins block?
Voltage-gated K⁺ channels (more Ca²⁺ influx - more release)
What does ziconotide act as?
A selective N-type voltage-gated calcium channel blocker
How is ziconotide given and what is it used for?
Given via the intrathecal route for the management of severe pain
What does synaptotagmin detect?
Increase in intracellular calcium
What is black widow spider venom?
α-latrotoxin (α-LTX)
What happens to the synapses when exposed to α-LTX?
Massive ACh release which causes muscle spasms
What happens to the synapses after being exposed to α-LTX?
Depletion of vesicle pool
Desensitisation of neuromuscular junction
Inhibition of endocytosis
Distended terminal
Paralysis
What is the effect of an α-LTX dimer?
Enhances calcium ion intake into the synapse
What is the effect of an α-LTX tetramer?
Forms calcium ion channel in the synapse
What does the release of each quanta of transmitter at a NMJ give rise to?
A miniature end plate potential (mEPP) via activation of nAChRs
What do mEPPs summate to give?
An end plate potential (EPP), which, if large enough, can initiate an action potential and hence muscular contraction
What terminates the activation of nicotinic ACh receptors at NMJ?
Acetylcholinesterase (AChE/AChase)
What drugs inhibit AChE?
Anticholinesterases (eg nerve agents, neostigmine)
Increase the concentration and effects of ACh - can lead to muscle spasms
What is tubocurarine?
Competitive non-depolarising blocker (antagonist)
Arrow poison - kills prey by respiratory paralysis
What are the clinical side effects of tubocurarine?
Decreased BP due to ganglion block & resultant vasodilation
What are the names of the two competitive non-depolarising blockers in clinical use?
Vecuronium & Rocuronium (few side effects)
Is vecuronium or rocuronium rapid in onset?
Rocuronium
What are all competitive non-depolarising blockers reversed by?
Anticholinesterases eg neostigmine
What occurs in phase I block?
- Persistent activation of endplate nicotinic - receptors by suxamethonium
- Prolonged depolarisation of endplate
- Inactivation of voltage-gated sodium channels
What occurs in phase II block?
- Desensitisation of endplate nicotinic receptors
- Repolarisation of endplate
- Receptor desensitisation maintains blockade
What is suxamethonium?
Depolarising blocker (agonist)
Used clinically
Rapid onset of paralysis
Short duration – broken down by plasmacholinesterases
Tracheal intubation, electroconvulsive therapy
What are the side effects of suxamethonium?
Bradycardia (decreased heart rate) due to M2 mAChR activation in heart
K⁺ release in trauma (eg burns) – cardiac dysrhythmias & cardiac arrest
Prolonged paralysis (2hr+) in 1:3500 people
What do ganglion blockers do?
Reduce the actions of both the sympathetic and parasympathetic nervous systems
At the neuromuscular junction, what does the activation of nicotinic receptors promote?
Skeletal muscle contraction and underpins physical movement and breathing
What can drugs that block nicotinic neuromuscular transmission be used for?
Can be used in surgery to prevent unwanted muscular contractions, but by two different mechanisms
What can drugs that block nicotinic receptors at the autonomic ganglia be used for?
Lowering blood pressure
