The neuromuscular junction contains specialized anatomical structures that allow for efficient neurotransmission between a motor neuron and muscle fiber. It consists of a presynaptic nerve terminal, synaptic cleft, and postsynaptic end plate on the muscle fiber membrane. Acetylcholine is released from vesicles in the nerve terminal in response to an action potential and binds nicotinic receptors on the end plate, allowing sodium and potassium ions to flow and depolarize the membrane. This end plate potential can trigger an action potential in the muscle fiber, causing contraction. Acetylcholine is then broken down by acetylcholinesterase to allow the muscle to relax until the next action potential.

1. NMJ Physiology
Dr MUHAMMAD SHAFI K
DNB RESIDENT,RENAI MEDICITY
MODERATOR
Dr. Ashwin Lawrence Luiz

2. Neuromuscular Junction
➢ neuromuscular junction contains the distal nerve terminal, Schwann cell,
synaptic cleft, and muscle end plate
➢ prototypical and most extensively studied synapse and receptor.
➢ Transmission;acetylcholine as small, uniformly sized packages called vesicles
➢ vesicles are congregated in the portion toward the junctional surface,
➢ microtubules, mitochondria, and other support structures are located toward
the opposite side

3. ANATOMY

4. STRUCTURE
● Terminal button
● Presynaptic membrane
● Synaptic cleft
● Postsynaptic membrane

5. PRESYNAPTIC PORTION
● Neuron innervating skeletal muscle fibre – Motor Neurons Near muscle fibre it looses its
myelin sheath & divides into axon terminals
● Each terminal is expanded at its tip to form Synaptic Knob ( Terminal Button)
● The motor neuron its axon, its terminal with muscle fibre it supplies – form MOTOR UNIT.
● Terminal button lies in a groove- Synaptic Trough.
● Vesicles gather at specific points – Active Zones – Membrane at active zone modified to
form Dense Bars – contains numerous voltage gated Ca channels

6. SYNAPTIC CLEFT
● 50-100 nm wide.
● Filled with extracellular fluid
● Muscle fibre is covered by basement membrane or basal
lamina.
● It contains AchE (acetyl- choline-esterase) It hydrolyses Ach
into Acetate & Choline

7. POST SYNAPTIC MEMBRANE
● It’s a part of sarcolemma
● It is thrown into several folds – Junctional Folds so
● increases end plate membrane surface area.
● Contains Ach-receptors which contains voltage
gated nonspecific cation channels

8. Why EOM have peculiar NMJ?
❖ most adult human muscles have only one neuromuscular junction per cell,
❖ exception- extraocular muscles
❖ ocular muscles slowly contract and relax rather than quickly -they can maintain
a steady contraction
❖ depolarizing muscle relaxants (e.g., succinylcholine) affect them differently.
❖ long-lasting contracture response that pulls the eye -increase in IOP

9. Sequence Of Events At NMJ
Action potentials arriving at the presynaptic terminal cause voltage-
gated Ca2+ channels to open.
Lambert-Eaton
myasthenic
syndrome

10. Sequence Of Events At NMJ
Ca2+ uptake into the terminal causes release of the neurotransmitter acetylcholine
into synaptic cleft , which has been synthesized and stored into synaptic vesicles

11. Sequence Of Events At NMJ
■ Ach travels across the synaptic cleft to postsynaptic membrane which is
also known as motor end plate.

12. Sequence Of Events At NMJ
■ Motor end plate contains nAChR , which r ligand
gated ion channels
■ Ach binds to the alpha subunits of nicotinic
receptors and causes conformational change.
■ central core of channels opens & permeability of
motor end plate to Na+ & K+ increases
Myasthenia gravis

13. Sequence Of Events At NMJ

14. End plate potential
■ When the ion channel on post synaptic membrane opens
both Na+ & K+ flow down their concentration gradient.
■ At resting potential net driving force for Na+ is much greater
than K+ ,when Ach triggers opening of these channels more
Na+ moves inwards than K+ out wards, depolarizing the end
plate.this potential change is called end plate potential (EPP).
■ EPP is not an action potential but it is simply depolarization of
specialized motor end plate

15. End plate potential
■ Small quanta (packets) of Ach are released randomly from
nerve cell at rest, each producing smallest possible change in
membrane potential of motor end plate, the MINIATURE EPP.
■ When nerve impulse reaches the ending, the number of
quanta release increases by several folds and result in large
EPP.
■ EPP than spread by local current to adjacent muscle fibers
which r depolarized to threshold & fire action potential
15

16. SYNAPTIC VESICLES AND RECYCLING
● releasable pool and a reserve pool, sometimes called VP1 and VP2
● VP2 are a bit smaller and limited to an area very close to the nerve membrane,
where they are bound to the active zones
● SNARE proteins are involved in fusion, docking, and release of acetylcholine.
● larger reserve (VP1) vesicles,deep from the nerve ending and firmly tethered to
the cytoskeleton
● During increased need-HIGH Ca2+ influx->>mobilization of VP1 pool.

17. Synaptic vesicle
❖ active zones or release sites.

18. PROCESS OF EXOCYTOSIS
● action potential >>calcium ions
enter>>Synaptotagmin detects>>synapsin
becomes phosphorylated, >> frees the
vesicle.
● synaptobrevin on the vesicle forms a
ternary complex with syntaxin and SNAP-
25
● Botulinum neurotoxin selectively digests
one or all these SNARE proteins

19. POSTJUNCTIONAL ACETYLCHOLINE
RECEPTORS
● Three isoforms
1. a junctional or mature receptor-confined to the end-plate region
2. an extrajunctional or immature (fetal) receptor, expressed anywhere on the
muscle membrane
3. neuronal α7 nicotinic receptor- immobilization, sepsis,burn injury and
denervation
4. synthesized in muscle cells and are anchored to the end-plate membrane by
rapsyn

20. ● The fetal (immature, extrajunctional)
receptor consists of α1-, β1-, δ-, and γ-
subunits; there are two subunits of α and
one each of the others.
● Mature receptor consists of α1-, β1-, δ-,
and ε-subunits,
● The neuronal α7 AChR consists of five α7-
subunit
HYPERKALEMIA

21. ● Upper and Lower motor
denervation and
● burns
● sepsis
● immobilization
● chronic muscle relaxant
therapy or
● botulism
● loss of muscle electrical
activity).

22. PREJUNCTIONAL ACETYLCHOLINE
RECEPTORS
● Nicotinic AChRs
1. Nm classic muscle-type nicotinic AChR is postsynaptically
2. Nn neuronal subtype receptors may be presynaptically and
postsynaptically
● only α- and β-subunits.
● peripheral and central nervous systems, on autonomous nerves and ganglia on
oxygensensing cells within the carotid bodies.
● form and functions are not as completely understood.

23. Functions
● HOW NDMRs Prevent fasciculations produced by SCh?
● stimulated by SCh and neostigmine and depressed by small doses of
nondepolarizing NMBDs.
● fade phenomenon-tetanic or train-of-four stimulus patterns- inhibition of α3β2-
subtype.
● positive-feedback system causes the release of more transmitters
● negative-feedback system shuts down the release system.

24. BASIC ELECTROPHYSIOLOGY OF
NEUROTRANSMISSION
● pore of the channel is closed by approximation of the cylinders (i.e., subunits).
When an agonist occupies both α-subunit sites, the protein molecule
undergoes a conformational change.
● Both α-subunits must be simultaneously occupied by agonist
● central channel is open, sodium and calcium flow from the outside of the cell
to the inside and potassium flows from the inside to the outside.
● current transported by the ions depolarizes the adjacent membrane.
● net current is depolarizing and creates the end-plate potential that stimulates
the muscle to contract.

26. ANATOMY

27. sodium channel
● Dual gated
● upper bar is voltage dependent; the lower bar is time dependent
● three functional conformational states

28. Acetyl cholinesterase
■ When stimulus ends acetylcholinestrase(AchE) degrade Ach
to choline & acetate
■ About 50%of choline is returned to the presynaptic terminal
by Na+choline transport to be reused for Ach synthesis.
■ Now muscle fiber can relax ,if sustained contraction is
needed for the desired movement another motor neuron AP
leads to release of more Ach

29. Neuromuscular Junction at Extremes of Age

30. THANKS