Neuromuscular Junction Flashcards
Components Neuromuscular Junction
Lower motor neuron
Muscle fibre
Regions of NMJ
Presynaptic region
Synaptic cleft
Postsynaptic region
What is a motor unit
One motor neuron, axon, presynaptic termini, muscle fibres
One motor neuron and all the fibres it innervates
What is the innervation ratio
Number of muscle fibres supplied by one motor neuron
Large innervation ratio- large motor unit
How are motor units recruited
As needed- small first
- diff threshold activation
Steps for action potential propagation between neurons
- Neurotransmitter synthesized and packaged into vesicles
- Action potential arrives at presynaptic terminal
- Voltage gated Ca channels open. Ca enters
4.rise in Ca triggers fusion of synaptic vesicles with the presynaptic membrane - Neurotransmitter diffuse across synaptic cleft and bind to specific receptors on postsynaptic cell
- Bound receptors activate postsynaptic cell
7.neurotransmitter breaks down, is taken back up by presynaptic terminal or other cells, or diffuses away from the synapse
Note: axon terminus unmyelinated
Function presynaptic termini
Synthesis, storage and release of ACh
Stored in synaptic vesicles
How is ACh made
Choline and acetyl-CoA
Enzyme: choline acetyltransferase (ChAT)
How much ACh can one vesicle store
Quantum 6,000-10,000
“quantal release of ACh”
Where are vesicles stored
Immediate or secondary storage areas
What type of Ca channel is on presynaptic membrane
P-type Ca channel
Where can vesicles fuse (dock) at presynaptic membrane
Specific sites called active zones
What steps must happens to vesicle before fusion with presynaptic memrbane
Primed, Cocked, armed
Involves 25 proteins
What is the kiss and run mechanism
Recycles vesicles for reloading and reuse
Kiss- slight connection
Run- back into presynaptic neuron. Vesicle doesnt become part of membrane stays whole
What compounds are used in the docking phase of synaptic release and what is their function
v-SNARE= synaptobrevin
t-SNARES= syntaxin, SNAP-25
Form a zippered complex bringing the vesicle and target into proximity
What primes the complex after docked stage
Complexin
Explain the details of kiss phase
Ca enters and binds to synaptotagmin
Ca-synaptotagmin displaces complexin and binds the SNARE complex causing pore formstion (kiss) followed by release
Role of v-SNARES and t-SNARES with synaptic release
Form zippered complex bringing vesicle and target close together
Role of synaptotagmin
Ca binds to it. Together displace complexin and bind to SNARE complex causing pore formation
Explain details of run phase
Ca depletes causing synaptotagmin to dissociate from SNARE complex
SNARE complex disassembles
Vesicle endocytoses (run) back into neuron
What does tetanus toxin do and cause
Cleaves synaptobrevin
Causes rigid paralysis by blocking GABA (fn- inhibit neuronal transmission- reduce excitability) release
(TNTX)
What does Botulism toxin do and cause
Cleaves synaptobrevin at NMJ (therefore no ACh release)
Causes flaccid paralysis- no contraction at all
(BTX)
How is Ca removed from pre synaptic neuron after synaptic release
Extrusion by plasma membrane Ca ATP-ase (PMCA) and uptake by mitochondria
Name the post synaptic receptor and what binds to it
Nicotinic acetylcholine receptor (NAChR)- transmembrane protein
2 ACh bind
Name subunits of NAChR
2 alpha, 1B, 1 delta, 1 epsilon
Heteromeric pentamer
What ions move through NAChR
Na move down electrochemical gradient
When ___ moves through the NAChR it produces a ___
Na
Passive end plate potential (EPP) (graded/passive)
What type of channel is NAChR
GPCR- ligand gated channel (ligand- ACh)
Name types of ion channels in muscle (postsynaptic structure)
AChR
Na channel (voltage gated)
Cl- channel
K channel
Ca channel (not as channel but important- DHP mechanically coupled)
What are mEPPs and when do they occur
Miniature end plate potentials
Occur spontaneously at motor end plate- due to spontaneous release of vesicles (ACh) without action potentials
Normal occuramce doesn’t lead to AP
mEPPs are additive
What did the discovery of EPPs allow for
Determine quantal basis of synaptic release at NMJ
What allows Ca to enter pre synaptic neuron
Increase in intracellular permeability to Ca
Enter via voltage gated Ca channels
What causes EPP and what does it do
Increased permeability of Na and K
EPP depolarizes areas of muscle membrane adjacent to end plate - this initiates AP in muscle
What can inhibit neuronal Na channels
Tetrodotoxin (puffer fish)= loss of sensation, paralysis of voluntary muscles, respiratory failure
Saxitoxin (algae- shellfish) tingling/burning, shortness of breath
What inhibits K channels
What does this compound enhance
Dendrotoxin (snake)
Enhances ACh release, muscle hyperexcitability, convulsions
What inhibits ACh release
What does it cause
Tetanus toxin (rigid paralysis)
Botulinum toxin (flaccid paralysis)
What inhibits acetylcholinesterase
Physostigmine
DFP
What inhibits AChR channel
What does it cause
D-tubocurarine
Alpha- bungarotoxin (snake) = paralysis, respiratory failure, death at high doses
What compounds activate AChR channel
Nicotine
ACh (acetylcholine)
What inhibits muscle Na channel
Tetrodotoxin
Saxitoxin (algae- paralytic shellfish poisoning) = tingling/ burning, shortness of breath
U-conotoxin
What inhibits Ca channels
w-conotoxin
What is myasthynia gravis and what does it target
Autoimmune disease targets postsynaptic NMJ= motor end plate (degenerates)
What does myasthynia gravis cause in the body, symptoms, treatments
Causes Substantial loss of junctional folds- reduced number of NAChR
Symptoms impaired neuromuscular transmission, weakness of facial and body muscles
Treatments- acetylcholinesterase inhibitors (keep ACh around longer), immunosuppressants
Symptoms of individual who has a neuromuscular transmission disorder
Weakness of cranial and skeletal muscles
Clinical manifestations of myasthenia gravis
Diplopia- double vision
Ptosis- drooping upper eyelid
Weakness of facial, bulbar, respiratory, proximal limb muscles
