L1 - Neuromuscular Junction Flashcards
What is ptosis?
Drooping of the upper or lower eyelid
What is a transmission disorder?
Faulty communication between nerves and muscles that leads to muscle weakness
What are 3 types of transmission disorder?
Axon fails to deliver strong signal
Fibre fails to respond to signal
Enhanced signal leads to uncontrolled activation
How does the neuromuscular junction work?
- action potential arrives to sarcoplasmic reticulum (SR)
- release of Ca
- muscle contracts
What three cells are involved in the NMJ?
Motor neuron
Schwann cell
Muscle cell
What neurotransmitter is present on the NMJ?
Acetylcholine
What is between the neuron and the muscle cell?
Basal lamina
What is the basal lamina?
Connective tissue crucial for maintain structure of NMJ and its function
What enzyme is in the basal lamina and what else is there?
Acetylcholinesterase associated with collagen
What structure is on the postsynaptic membrane and why?
Deep infolding of the sarcolemma (secondary synaptic folds) with anchored AChRs on the crests.
Accumulate as much receptor as possible and increase efficiency of transmission
What does acetylcholinesterase do?
Hydrolyses acetylcholine to transport it back into nerve terminal.
A serine in the active site does it
Why is acetylcholinesterase involved in disease?
Nerve gases and neurotxoins inhibit it by reacting with the same Serine - extending the period of membrane depolarisation
What are the two major events in development of NMJ?
- Receptors aggregating into clusters
2. Specialisation of nuclei sitting right underneath junction along muscle fibre
How many more AChRs are at the NMJ?
1000x more concentrated than at extra synaptic places
What experiment was used to show clustering of receptors?
Removed nerve and muscle fibre leaving only basal lamina
Signal sufficient for formation of synaptic folds rich in ACh
What fish was used to investigate thw NMJ and why?
Electric ray
Has 500 end places capable of releasing electric currents of 100V
What protein was eventually found to promote clustering?
Agrin
What are the features of agrin?
400 kDa proteoglycan
Secreted by motor neuron, muscle and schwann cell
Promotes clustering of AChR without enhancing AChR syn
What is the ratio of agrin to AChR at the NMJ and what does this show?
1:50 - 1:100
Clustering through signal rather than structural constraints
What was found to be the agrin receptor?
MuSK (muscle specific kinase)
How does agrin induce clustering?
- Agrin interacts with MuSK, Masc complex
- Musk is a receptor tyrosine kinase
- MuSK activation leads to phosphorylation of rapsyn - a scaffolding protein and clusters AchRs
What is rapsyn?
A scaffolding protein that clusters AChRs
What is MASC and what is its function?
myotube associated specificity component
Required to form agrin receptor
What occurs in Lambert-Eaton syndrome?
Autoantibodies to P/Q-type voltage gated calcium channels
What is hypothesised to be the origin of autoantibodies in Lambert-eaton?
Too much exposure to own protein
VGCCs known to be expressed by small cancer lung cells often present in this syndrome
What is the function impaired in Lambert-Eaton syndrome>
Downregulation of presynaptic Ca channels causes myasthenia by preventing NT release - not enough fibres firing
What occurs in Isaac’s syndrome?
Autoantibodies to Voltage gated potassium channels
What are the internal symptoms of Isaac’s syndrome
Increased NT release so persistent depolarisation enhanced muscle contraction
What are the external symptoms of Isaac’s syndrome?
Painful cramps and spasms
What occurs in congenital myasthenic syndrome associated with episodic apnoea?
Mutations in CHAT impair catalytic efficiency of enzyme
What are the features and function of CHAT?
Located in terminals of cholinergic neurons
Catalyses reversible syn of acetylcholine from acetyl CoA and choline
Why causes acetylcholinesterase deficiency?
Mutations in collagen tail that anchors AChE
What are the internal symptoms of acetylcholinesterase deficiency?
Persistent presence of Ach in cleft causing repetitive binding to AChRs causing muscle fatigue and endplate myopathy
What do defects in repolarisation of the presynaptic membrane or elimination of ACh from cleft lead to?
Excessive transmission
What causes Seronegative myasthenia gravis?
Antibodies against MuSK
What causes congenital myasthenic syndrome?
Mutations in rapsyn
What are the internal symptoms of Myasthenia gravis and myasthenic syndrome?
Inhibition of agrin-MuSK signal destabilises NMJ
What causes postsynaptic congenital MG?
3 types of mutations in AChR genes
What are the 3 types of mutations in AChRs?
Slow channel syndrome
Fast Channel Syndrome
ACh deficiency
What is Slow channel syndrome?
channel takes longer to close and too much influx of NA takes place
What is Fast channel syndrome?
channel closes too quickly and not enough depolarisation
What is ACh deficiency?
Causes AChR to be unstable resulting in reduced receptors and deficient transmission
What are the external symptoms of Myasthenia gravis?
Strong in the morning but progressively weaker through day because of depletin of ACh
What is found in 80-90% of patients with MG?
Anti-AChR antibody
What causes neonatal MG?
Placental transfer of maternal AChR antibodies
What is arthrogryposis multiplex congenita?
MG associated in rare cases
Occurs when maternal AChR antibodies target fetal form
What does arthrogyrposis multiplex congenita cause and how?
Bent hands and feet due to excessive tendon force
Maternal antibodies had attacked fetal AchRs so contractinos crucial for development were not there
What does affecting the postsynaptic targets generally lead to?
Impaired transmsion and muscle weakness
What are the postsynaptic targets?
Rapsyn
MuSK
AchRs
What are the presynaptic and sypantic targets?
VGCC, VGKC, CHAT, ACHE
What are treatments of MG?
Cholinesterase inhibitors
Thymectomy
Medication to alter immune sys
Immunoglobulin therapy
In congenital myasthenia gravis what is the treatment of a reduced response?
Cholinesterase inhibitors
In congenital myasthenia gravis what is the treatment of a increased response?
Open channel blockers of the AChR are used
