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 neuromuscular junction with a muscle fiber at its mid-point. NMJ is a chemical synapse.**

NEUROMUSCULAR JUNCTION (NMJ)

At NMJ, muscle fiber is called 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)

End foot has: Mitochondria & presynaptic 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 is present.

Mechanism of neuro-muscular transmission:

Mechanism of neuro-muscular transmission:

Nerve impulse reaches the nerve terminal opening of voltage gated calcium channels. Calcium (from ECF) enters nerve terminal agitation of some of the synaptic vesicles (125 -150 vesicles become agitated & fuse with membrane) release their acetylcholine into synaptic cleft by exocytosis. Ach (released) binds with receptors at motor end plate opening of Ach gated channels sodium influx end plate potential (EPP) (which is localized potential change).

End plate potential (EPP)

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) 2. Not propagated but decremental with distance

Independent of stimulus strength (all or none) 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. Ach (on hydrolysis) Choline + Acetate

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 liberate Ach 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 receptors & these receptors are destroyed irreversibly.

Clinical features of Myasthenia Gravis

weakness of Extraocular 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 (neostigmine, 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 patients blood. 2. In many of these cases, thymus is enlarged & thymectomy is of benefit.

DESCRIPTION OF a typical 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 motor neurons. The woman is diagnosed with myasthenia gravis and is treated with the drug neostigmine. 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.