Lecture 1 Flashcards
(36 cards)
What type of disorders are no longer life threatening?
Transmission Disorders
What are myasthenic syndromes?
Muscle weakness syndromes due to faulty communication between nerves and muscles
How does an action potential cause muscle contraction?
Acetylcholine released from axon across synaptic cleft and an action potential is created in the muscle, this potential diffuses across the sarcolemma and down the T tubule triggering and efflux of Ca2+ from the sarcoplasmic reticulum. Calcium ion bind to troponin and change its shape, removing tropomyosin and freeing the active sites of the actin. Myosin cross bridges attach and detach from the actin filaments pulling the actin towards the sarcomere, using ATP. Calcium ions removed by actin transport into the SR after the action potential ends and the tropomyosin blockage is restored.
What are the three types of cell at the neuromuscular junction?
The axon, the muscle and the schwann cells
What is the transmitter?
Acetylcholine
What part of the muscle make sup the synaptic cleft?
A specialised region of the basal lamina
Where are the the receptors for the ACh found?
At the top of the folds in the postsynaptic terminal
Where are the voltage gates sodium channels located?
At the bottom of the folds
How is ACh release stimulated when the pre synaptic terminal is depolarised?
Voltage gated calcium channels open and the influx of calcium ions causes ACh vesicles to fuse with the membrane and release their contents
What happens due to ACh binding to its receptors on the post synaptic site?
The receptors are also sodium channels, allowing sodium influx due to binding causing local membrane depolarisation on the post synaptic site. The depolarisation travels down the folds and hits the voltage gated sodium channels, if the depolarisation is large enough then the sodium channels will open, triggering a post synaptic potential causing muscle contraction but calcium release from sarcoplasmic reticulum.
How is ACh release by the pre synaptic membrane stopped?
Potassium channels open and stop the depolarisation and hence stop calcium influx
How is ACh removed from the cleft?
Acetylcholinesterase (ACHE) degrades ACh
Describe ACh receptor distribution on muscle fibre in embryonic development and in adults
10/square µm in embryonic and 10000/square µm in adult
How was it shown that the basal lamina directs clustering of the ACh-R’s?
Denervation and muscle elimination leaves on the basal lamina and the muscle satellite cells, allowing new muscle fibre to form in which the the ACh-R’s cluster to same site as the original neuromuscular junction, but without a motor neuron.
How does the basal lamina direct this clustering?
A chemical signal that has been retained at the site, probably originally from the motor neuron, is still sufficiently strong to orchestrate this process
What is the chemical signal that allows AChR clustering?
Agrin
400kDa proteoglycan component of the basal lamina, secreted by motor neuron, muscle and schwann cells but neuronal form is 1000X more effective. Promotes AChR clustering without enhancing AChR synthesis
Outline the role of Agrin
Agrin interacts with MuSK/Masc. MuSK activation leads to phosphorylation of rapsyn which causes clustering of the AChR’s
Why was it known that another protein must be involved? What is this protein?
Simply providing activated MuSK was not sufficient to cause the same level of clustering as adding Agrin. Dok7 was found to also be important; activating MuSK’s phosphorylation potential
What are the two types of diseases of the neuromuscular junction?
Acquired, auto antibodies against important components on the cell surface of the neuromuscular junction, or genetic, mutations in any important component
What one possible route has been put forward for the creation of auto antibodies?
Over expression of the component, e.g. voltage gated sodium channels are over expressed by some cancers, and once the cancer is gone antibodies for the channels still exist and now target the neuromuscular junction.
What causes Lambert-Eaton myasthenic syndrome? What effect does it have on transmission?
Antibodies againt P/Q type VGCCs (Pre synaptic)
Depressed transmission; ACh not released into the cleft
What causes Isaac’s syndrome? What effect does it have on transmission?
Antibodies against VGKCs (Pre synaptic)
Increased transmission; no re polarisation of pre synaptic cleft so continuous release of ACh
What causes congenital myasthenic syndrome associated with episodic apnoea? What effect does it have on transmission?
Mutations in CHAT; catalyst for reversible synthesis of acetyl choline from acetyl CoA and choline. (Pre synaptic)
Vesicles are not refilled so as day goes on they have depressed transmission
What is the miniature end plate potential? Why is it used?
MEPP is a small depolarisation (~0.5mV) caused by release of the contents of a single ACh vesicle. Used to give indication of amount of ACh in vesicles.
