NEURO-MUSCULAR JUNCTION

By

Dr. Mudassar Ali Roomi (MBBS, M. Phil)

NEUROMUSCULAR JUNCTION (NMJ)

• Motor nerve fibers which supply the muscle lose their myelin sheath near muscle fiber.

• Then terminal part divides

into motor nerve terminals / end feet / synaptic knobs.

• Each end foot forms neuro-

muscular junction with a muscle fiber at its mid point.

• NMJ is a chemical synapse.**

NEUROMUSCULAR JUNCTION (NMJ)

• At NMJ, muscle fiber

thick motor end plate. Here is an invagination called as synaptic gutter.

• End foot fits into the gutter to form NMJ, but no continuity between nerve & muscle.

• Membrane of motor end

plate is thrown into folds sub-neural cleft.

NEUROMUSCULAR JUNCTION (NMJ)

NEUROMUSCULAR JUNCTION (NMJ)

• Synaptic clefts & sub-neural clefts are filled with basal lamina having fluid.

• End foot has: Mitochondria

& pre-synaptic vesicles with neurotransmitter: Acetylcholine.

• Vesicles are synthesized in

cell body & then transported to nerve terminal & mitochondria provide energy for it.

• In basal lamina is

Acetylcholine esterase enzyme.

Mechanism of neuro-muscular transmission:

Mechanism of neuro-muscular transmission:

• Nerve impulse nerve terminal depolarization of membrane of nerve terminal opening of voltage gated calcium channels in membrane.

• Calcium (ECF) End foot / nerve terminal agitation of some of

the synaptic vesicles (125 -150 vesicles become agitated & fuse with membrane) break their acetylcholine into synaptic cleft by exocytosis.

• Ach (released) binds with receptors (part of protein molecules) at

motor end plate (Ach gated channels/ cholinergic receptors/ ligand gated channels) of nicotinic type at motor end plate opening of Ach gated channels sodium influx EPP (localized potential change). It is graded (amplitude is directly proportional to amount of Ach released). Not self propagated, so decrease with distance. Prolonged in duration.

• 50-70 mV is amplitude of EPP. • Because of EPP Threshold for action potential is

reached (-65 mV). • If RMP is -90 mV, then threshold is -65 mV, we need

25 mV potential change. • Purpose of EPP is to reach the threshold of action

potential. • So voltage of EPP is much more than required,

because required is only 25 mV. It is called as SAFETY FACTOR.

End plate potential (EPP) Action potential

1. Proportional to stimulus strength (graded)

Independent of stimulus strength (all or none)

2. Not propagated but decremental with distance

Propagated, unchanged in magnitude

3. Exhibits summation Summation not possible

4. magnitude: low Magnitude: high

5. Refractory period: absent Refractory period: present

6. duration: Longer duration: shorter

How the action of Acetylcholine is finished??

• Ach once released, remains bound with receptors only for 1 msec.

• Some diffuses out to ECF &

rest is hydrolyzed by enzyme acetylcholine esterase of sub-neural cleft.

• Ach (on hydrolysis) Choline

+ Acetate • So that new impulse can be

transmitted through NMJ.

• These channels have 5 sub-units:

2 alpha sub-units which protrude out on surface &

3 others are beta, gamma & delta.

• Ach synthesized in synaptic knob vesicle released recycled.

• Mitochondria energy Ach formation from CoA & Choline synaptic knob.

• Impulse reaches agitation of vesicles Ach binds with receptors Ach esterase acetate & choline recycled.

MYASTHENIA GRAVIS:

• A rare auto-immune disease. • More common in females • Voltage of EPP is very low (Miniature EPP) action

potential is not followed. At rest normally, a few synaptic vesicles break to liberate Ach from synaptic vesicles small change in EPP (about 0.5 mV) called MEPP.

• Impulse fails to transmit through NMJ Severe muscle

weakness & fatigue.

• Auto-antibodies are produced against Ach gated receptor channels & these receptors are destroyed irreversibly, though Ach is present

Clinical features of Myasthenia Gravis

• weakness of Extra-ocular muscles ptosis (drooping of upper eyelids), diplopia (double vision)

• difficulty in Swallowing,

• weakness of Respiratory and Facial muscles

TREATMENT of Myasthenia Gravis

1. Anti-cholinesterase drugs (Physostigmine) marked improvement.

– Mechanism of action: anticholine esterases

inhibit enzyme choline esterase Ach not hydrolyzed more Ach available for available number of receptors.

2. Plasmapharesis: it may sometimes be needed to remove the autoantibodies from the serum.

3. Glucocorticoids (steroids) may also be required to inhibit the immunity.

Evidence that Myasthenia Gravis is an autoimmune disease:

1. Auto antibodies detected in patient’s blood.

2. In many of these cases, thymus is enlarged & thymectomy is of benefit.

3. If mother is myasthenic, newborn shows features of myasthenia for few weeks because antibodies cross the placenta. But antibodies die in few weeks, due to limited life span. They will destroy few receptors, which will regenerate later.

DESCRIPTION OF a CASE of Myasthenia Gravis

• An 18-year-old college woman comes to the student health service complaining of progressive weakness. She reports that occasionally her eyelids "droop" and that she tires easily, even when completing ordinary daily tasks such as brushing her hair. She has fallen several times while climbing a flight of stairs. These symptoms improve with rest. The physician orders blood studies, which reveal elevated levels of antibodies to ACh receptors. Nerve stimulation studies show decreased responsiveness of skeletal muscle upon repeated stimulation of motoneurons. The woman is diagnosed with myasthenia gravis and is treated with the drug pyridostigmine. After treatment, she reports a return of muscle strength.

EXPLANATION OF CASE

• This young woman has classic myasthenia gravis. In the autoimmune form of the disease, antibodies are produced to ACh receptors on the motor end plates of skeletal muscle.

• Her symptoms of severe muscle weakness (eye muscles; arms and legs) are explainable by the presence of antibodies that block ACh receptors. Although ACh is released in normal amounts from the terminals of motoneurons, binding of ACh to its receptors on the motor end plates is impaired. Because ACh cannot bind, depolarization of the motor end plate (end plate potential, EPP) will not occur, and normal action potentials cannot be generated in the skeletal muscle. Muscle weakness and fatigability ensue.