A brief overview of the physiology of the neuromuscular junction.It includes a video towards the end sourced from the internet with the copyright watermarks intact.
4. The Motor Unit
Each motor neuron from the ventral horn runs
uninterrupted up to the muscle
Splits into a functional group called the motor unit
Single neuron supplying a group of muscle fibres
Contract and relax as a unit
10. Anatomy
Branching nerve terminals invaginate into the
surface of the muscle fibre but lie outside the
sarcolemma
Hence the synaptic cleft
Usually around 20-30 nm
ACh receptors on the post junctional
membrane
11.
12. Acetylcholine receptors
Nicotinic
Cation channels
Junctional or mature
Extra junctional or immature or fetal
Usually after muscle fibre injury
Within 18 hours
Altered response to NMJ blocking drugs
Sodium & Calcium moves in
Potassium moves out
13.
14. The Immature Receptor
Increased sensitivity to depolarizing agents
Decreased sensitivity to non-depolarizing agents
Stays open for a longer time
Hence increased efflux of intracellular potassium
Altogether can cause lethal hyperkalemia
15. ACh (Synthesis, storage, release)
Synthesized in the Presynaptic terminal from substrate Choline and Acetyl CoA.
CAT
CHOLINE + ACETYL CoA ACETYL CHOLINE
COMT
50% Carrier Facilitated Transport Release
CHOLINE + ACETYL CoA ACETYL CHOLINE
Synaptic Cleft
16. Different subsets of ACh vesicles
Immediately releasable stores, VP2:
Responsible for the maintainence of transmitter release under conditions of low
nerve activity
1% of vesicles
The reserve pool, VP1:
Released in response to nerve impulses
80% of vesicles
The stationary store: The remainder of the vesicles.
17. Acetylcholine
One vesicle contains approx. 12,000 molecules of ACh
Loaded by active transport- Mg2+ dependent H+ ATPase
A single vesicle equals a quantum ACh.
18. Nerve impulse
reaches the terminal
Calcium channels
open up
Ca2+ moves into the
terminal
Stimulates exocytosis
of ACh vesicles at the
active site
19. Replenishing the vesicles
Discharged vesicles are rapidly replaced from reserve stores
Reserve vesicles anchored to cytoskeletal actin by syanpsins
Ca2+ entry during initial discharge process also binds to
calmodulin
Stimulates protein kinase-2 which phosphorylates synapsins
Reserve vesicles are thus freed
20. Docking of the vesicle and subsequent discharge of acetylcholine by
exocytosis, involves several other proteins.
Membrane protein called SNAREs (Soluble N-ethylmatrimide sensitive
attachment proteins) are involved in fusion, docking, and release of
acetylcholine at the active zone.
SNARE includes – synaptic vesicle protein synaptobrevin, synataxin and
SNAP-25.
21.
22.
23. The released acetylcholine diffuses to the muscle type nicotinic acetylcholine
receptors which are concentrated at the tops of junctional folds of
membrane of the motor end plate.
Binding of acetylcholine to these receptors increases Na and K conductance
of membrane and resultant influx of Na produces a depolarising potential,
end plate potential.
The current created by the local potential depolarise the adjacent muscle
membrane to firing level.
26. Acetylcholine is then removed by acetylcholinesterase from synaptic cleft,
which is present in high concentration at NMJ.
Action potential generated on either side of end plate and are conducted
away from end plate in both directions along muscle fiber.
The muscle action potential in turn initiates muscle contraction
27. The Sodium Channel
Cylindrical
Its two ends act as gates
Both should be open to allow passage of ions
Voltage dependent gate is closed in resting state and opens
only on application of a depolarizing voltage, remains open
as long as the voltage persists
28.
29. The time dependent gate is normally open at rest closing a few milliseconds
after the voltage gate opens and remains closed as long as the voltage gate
is open
It reopens after the voltage gate closes.
The channel is patent, allowing sodium ions only when the gates are open.
30. Na channel states
• Resting state: Voltage gate closed
Time gate open
Channel closed
• Depolarization: Voltage gate open
Time gate open
Channel open
• Within a few milliseconds: Voltage gate open
Time gate closed
Channel closed
• End of depolarization: Voltage gate closed
Time gate open
Channel closed
31. The Role of Calcium
The concentration of calcium and the length of time during which it flows into the
nerve ending, determines the number of quanta released.
Calcium current is normally stopped by the out flow of potassium.
Calcium channels are specialized proteins, which are opened by voltage change
accompanying action potentials
32. Part of calcium is captured by proteins in the endoplasmic reticulum & is
sequestrated.
Remaining part is removed out of the nerve by the Na/Ca antiport system
The sodium is eventually removed from the cell by ATPase
33. Acetylcholinesterase
This protein enzyme is secreted from the muscle, but remain
attached to it by thin stalks of collagen, attached to the
basement membrane.
Acetylcholine molecules that don’t interact with receptors
are released from the binding site & are destroyed almost
immediately by acetylcholinesterase, in <1 ms, after its
release into the junctional cleft.
34. Extra ocular muscles
Tonic muscles
Multiple neuronal endings on a single muscle fibre
Contains immature receptors also
Reaction to depolarizing relaxant
Normal muscle – brief contraction followed by paralysis
Instead there is a long lasting contracture response
Pulls the eye against the orbit
Raises the IOP
39. References
Miller’s Anesthesia, 7th edition
Clinical Anesthesiology by Morgan, Mikhail and Murray, 4th
edition
Ganong’s Review of Medical Physiology, 23rd edition
Guyton and Hall: Textbook of Medical Physiology, 12th
edition
Editor's Notes
What is it?
a synapse is a structure that permits a neuron (or nerve cell) to pass an electrical or chemical signal to another cell (neural or otherwise).