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.

1. Physiology of The
Neuromuscular Junction
Presented by:
Dr. Ashwin Haridas

2. Neuromuscular Junction (NMJ)
Junction between a motor neuron and
its muscle fibre
A synapse
Motor end plate

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

6. Anatomy
The NMJ

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

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

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.

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.

25. ACh binds to
nicotinic
receptors
Increases
Na+ and K+
conductance
Depolarising
end plate
potential is
produced
Depolarises
the adjacent
sarcolemma
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

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

35. Contractile apparatus
 Thick and thin filaments
 Actin
 Myosin
 Troponin
 Tropomyosin
 Calcium
 The sarcomere

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