Lecture 10- The Neuromuscular junction Flashcards
The higher the frequency of AP, the more
ca2+ entry into presynaptic bouton
the more ca2+ entry into presynaptic bouton….
more NT released
the more NT released into the synaptic cleft…
the more likely to initiate AP above threshold in post synaptic neurone
outline how calcium promotes exocytosis of NT
- Action potential
- Opens voltage gated Ca2+ channels
- Ca2+ influx
- Increased [Ca2+]i
- Ca2+ binds to synaptotagmins
- NT vesicles brought close to the membrane
- Vesicles bind to Snare complex and makes fusion pore
- Content of vesicle diffuse into the synaptic cleft
voltage gated calcium channel has a similar structure to
NaV
calcium channels are
diverse- many different isoforms
name the 5 different types of calcium channel
L- type- muscle, neurones, lung
Blocked by DHP (dihydropyridines e.g. Nifedipine
N- type- neurone
P/Q- type- neurone
R- type- neurone
T- type- neurone, heart
properties of calcium channel
- CaV activate more slowly than Nav
- Can be activated and inactivated- slower than Na+ channel
- Inactivation is Ca2+ dependent.
- Increased intracellular [Ca2+] leads to inactivation of Ca2+ channels
the NMJ is the
synapse between nerve and skeletal muscle fibres
types of voltage gated channels in the nerve terminal
voltage gates Na+, K+ and Ca2+
when the membrane depolarises what happens to voltage gated calcium channels
calcium channels open causing influx
what is the motor endplarte
keletal muscle surface
- junctional folds increase the number of AChR –> increasing depolarisation
what degrades Ach in the synapse
AChesterase
what produces ACh
ACh transferase
outline synaptic transmission at the NMJ
- ACh from vesicle diffuses across the synaptic cleft and binds to Nicotinic (ionotropic) acetylcholine receptor (nAChR)
- Ligand gated receptor
- When 2 Ach binds to nAChR it allows ion sodium to enter the cell– depolarisation (end plate potential)
- Brief depolarisation of end plate will activate adjacent sodium channels due to local spread of charge causing muscle AP
- AP then initiates contraction of skeletal muscle fibre via excitation contraction coupling
NMJ and amazonian poison
Amazonian people use a poison called curare to hunt.
- Curare causes paralysis – easy to kill
- Blocks transmission at NMJ
- Eating curare is ok
myasthenia gravis is an
autoimmine disease, where antibodies target nAChR on the postsynaptic membrane on skeletal muscle
- a reduction in 30% of nAChR is sufficient to give symptoms
how do the antibodies destory the nAChR
by complement mediated lysis and receptor degradation
degradation of nAChR on the motor end plate causes
Endplate potentials are reduced in amplitude leading to muscle weakness and fatigue
what tes tis used to diagnose MG
endrophonium test
endrophonium test
- Facial weakness is provided by repeated facial movements (left)
- Edrophonium chloride (short acting anticholinesterase- increases conc of ACh in synaptic cleft) given via intravenous injection
positive endrophonium test
facial weakness rapdily relieved
where should edrophonium test be carried out
Test should always be done in a hospital where there are resuscitation facilities and with a drawn up syringe of atropine (a muscarinic receptor antagonist) present
organophosphate poisoning
- Organophosphates are used as insecticides (e.g. parathion, dimethoate)
- Accidental or self inflicted poisoning
- More powerful ones have been developed against nerve agents used in war or terrorism
name some organophosphate agents (synthetic) which have been developed against nerve agents used in war or terrorism
sarin
novickok
how do organophosphates cause poisoning
1) Inhibitors that form a stable irreversible covalent bond to ACh esterase
2) Recovery from poisoning may take weeks as synthesis of
new acetylcholinesterase enzymes are needed
ACh binds to both
nicotinic (somatic NS, ganglions) and muscarinic (parasympathetic) receptors
muscarinic receptors are
metabotropic
- slow
- GPCRs- second messenger cascade
how many types of mAChR
M1- exc
M2- exc
M3- inhib
M4- inhib
M5- exc
nAChR
Fast, Ligand-gated
Cholinergic, Ionotropic
Coupled to ion channels
Excitatory receptors
Two types
N1
N2
