Lecture 1, 2 & 3 - Physiology and Pharmacology of the Neuromuscular Junction Flashcards
What allows for communication at the synapse
The release of chemical messengers (neurotransmitters)
Where are neurotransmitters released from to allow communication at the synapse
The presynaptic nerve terminals
What do neurotransmitter act upon on the post synaptic membrane
Receptors
What are the five steps involved in the release of neurotransmitters
Synthesis, storage, release, activation and inactivation
What can affect the steps involved with the release of neurotransmitters
Drugs and toxins
Why are neurotransmitters stored
For protection and so that the quantity of neurotransmitter released can be controlled
How can drug enhance synaptic transmission
By direct stimulation of postsynaptic receptors or by indirect action
What are examples of direct stimulation of synaptic transmission
Natural transmitters and analogues
What indirect action causes enhanced synaptic transmission
Increasing transmitter release and the inhibition of transmitter removal
How can drugs inhibit synaptic transmission
By blocking synthesis, storage or release of neurotransmitter from the presynaptic neurone and by also blocking post synaptic receptors
What are the two different types of drugs that act directly on receptors
Agonist and antagonists
What are agonists
Drugs, hormones or transmitters that bind to specific receptors and initiate a conformational change
Two important properties of agonists
Affinity and efficacy
What is the affinity of an agonist
The ability of the agonist to bind to the receptor
What is the efficacy of an agonist
The ability of an agonist, once bound to a receptor, to initiate a biological response
Since agonists bind and activate receptors they have both
Affinity and efficacy
Role of antagonists
They bind to receptors but do not activate them
Do antagonists have affinity and efficacy
The have affinity but lack efficacy
What is a competitive antagonist
It competes with the agonist for the agonist binding site on the receptor
How is a block by an antagonist reversed
By increasing the agonist concentration
How are synapses classified
By the neurotransmitter released from the presynaptic neurone
What is the classification of synapses where the presynaptic neurone is acetylcholine
Cholinergic
What are the receptors upon which ACh acts on known as
Cholinoceptors
What are the two classes of cholinoceptors
Nicotinic ACh receptors and muscarinic cholinoceptors
What activates nicotinic ACh receptors
ACh or nicotine
What activates muscarinic receptors
ACh or muscarine
What type of receptor is the nicotinic ACh receptor
Transmitter-gated ion channel
How do nicotinic ACh receptors operate
An agonist binds to the receptor which induces a rapid conformational change to open the channel. The channel is selective for certain ions and the signalling happens extremely fast.
What are the nicotinic ACh receptors composed of
Separate protein subunits
What do the separate protein subunits of a nicotinic ACh receptor form
A central ion conducting channel
What do the separate protein subunits in a nicotinic ACh receptor allow for
Rapid changes in the permeability of the membrane to certain ions and rapidly alter membrane potential
Once the nicotinic ACh receptors are activated what does this also cause the activation of
The associated nicotinic cation channels
Once the nicotinic cation channels open what moves into the muscle fibre
Na+ ions
What does an influx of Na+ ions cause in the muscle fibre
Local depolarisation at the endplate region
What does motor nerve stimulation cause
The synchronous release of many vesicles, which causes the summation of MEPPs which go on to produce an EPP
What does the EPP cause
It depolarises the membrane potential to threshold
When the membrane potential is at threshold what is activated
Voltage-gated Na+ channels and this induces an action potential
How to calculate the quantal content
The mean EPP amplitude (mV) ÷ the mean MEPP amplitude (mV)
Do MEPPs or EPPS occur spontaneously
MEPPs
What is required to cause an EPP to occur
Motor nerve stimulation
What synthesises ACh from Acetyl Co-A and choline
Choline acetyl transferase (CAT)
Within the synapse where does the Acetyl Co-A come from
The mitochondria
What step is Na+ dependent
Reuptake of choline
What is the reuptake of choline blocked by
Hemicholinum 3
What blocks the transport of ACh into vesicles
The inhibition of the ACh transporter
What inhibits the ACh transporter
Vesamicol
What is the action of tertrodoxin (TTX)
It blocks the Na+ channels so no action potential can be generated
What blocks voltage-gated Ca2+ channels
Conotoxins
When voltage-gated Ca2+ channels are blocked what happens to the quantal content
The EPP amplitude decreases but there is no change in the MEPP amplitude so the quantal content decreases
What is the action of dendrotoxin
It blocks the voltage-gated K+ channel
What does the blockage of voltage-gated K+ channels cause
A prolonged action potential
How does dendrotoxin affect the quantal content
The EEP amplitude is increased but there is no change in the MEPP amplitude so the quantal content increases
What does botulinum toxin do
It blocks vesicle fusion so there is no release
How does botulinum toxin affect the quantal content
The EPP amplitude decreases and the MEPP amplitude remains the same so the quantal content decreases
What effect does turbocaranine have on muscles
It is a muscle relaxant
What is turbocaranine
A competitive non-depolarising neuromuscular blocking agent
What is turbocaranine reversed by
Anticholinesterases
What is alpha-bungarotoxin
An irreversible antagonist
What is suxamethonium
A muscle relaxant with rapid onset and a short duration
What is suxamethonium metabolised by
PLASMA ( i.e. butyric cholinesterase)
What is involved in the phase one block of suxamethonium
Persistant activation of endplate nicotinic receptors, prolonged depolarisation of the endplate and the inactivation of voltage-gated sodium channels
What is involved in the phase two block of suxamethonium
Desensitisation of endplate nicotinic receptor and depolarisation of endplate. The receptor desensitisation maintains the blockade.
Is suxamethonium an agonist or antagonist
Agonist
Where are true acetylcholinesterase found
At the cholinergic synapse, bound to the postsynaptic membrane
Where are pseudo-cholinesterases found
In plasma
What are pseudo-cholinesterases important in
Inactivating the depolarising neuromuscular blocker, suxamethonium
What inhibits both true and pseudo-cholinesterases
Anticholinesterases
What is neostigmine
An anticholinesterase
What action does neostigmine have on the quantal content
It increases both the amplitude of both the EPP and MEPP so there is no effect on the quantal content
What is the function of neostigmine
It prolongs the duration of the MEPP and EPP due to the increased life-time of ACh in the synaptic cleft
What do anticholinesterases do
The inhibit the breakdown of ACh by inhibiting acylecholinesterase
What are some clinical uses of anticholinesterase drugs
Reversal of neuromuscular paralysis, diagnosis and treatment of myasthenia graves and the treatment of Alzheimer’s disease
How is recovery from anticholinesterases achieved
A new enzyme has to be synthesised
What are dyflos
Volatile, non-polar, lipid-soluble molecules
What can reverse nerve gas
By atropine and oximes
What does atropine do
It counteracts the effects of excessive muscarinic receptor stimulation by ACh
What function do oximes have
To reactivate the AChase
