In this article we will discuss about:- 1. Meaning and Structure of Neuromuscular Junction 2. Mechanism of the Neuromuscular Transmission 3. Drugs Acting 4. Disorders.
Meaning and Structure of Neuromuscular Junction:
Neuromuscular junction (NMJ) is the junction between a motor neuron and a muscle fiber, through which action potential from the neuron is transmitted to the muscle fiber.
The structure of Neuromuscular junction can be broadly divided into three parts:
2. Synaptic cleft
3. Postsynaptic portions.
1. Presynaptic Portion:
i. Motor neurons that have their cell bodies in the anterior horn of spinal cord or brainstem innervate the skeletal muscle. Motor neuron axons are myelinated and are the largest diameter axons in the body.
ii. As the motor neuron axon approaches the skeletal muscle fiber it loses its myelin sheath and divides into number of fine branches (terminal axons) which end in small swellings (knobs) called terminal buttons, at the center of muscle fiber in the groove (synaptic trough) but outside the muscle fiber membrane.
iii. Each muscle fiber is supplied by one motor neuron terminal. The motor neuron plus the muscle fiber it innervates is called as motor unit.
iv. Terminal buttons (synaptic knobs) contains plenty of mitochondria and neurotransmitter vesicles. The acetylcholine (ACh) is synthesized in mitochondria and stored in vesicles.
v. The vesicles are clustered around a specific point called active zone, where voltage-gated Ca++ channels are present and mediate ACh release.
2. Synaptic Cleft:
i. This is gap between the terminal button and muscle fiber (50-100 nm wide).
ii. The basement membrane of muscle fiber in the cleft contains the enzyme acetyl cholinesterase, which hydrolyzes ACh into acetate and choline.
3. Postsynaptic Portion (End Plate Membrane):
i. The muscle fiber plasma membrane that lies directly under terminal axon portion is known as the end plate membrane (motor end plate).
ii. The endplate membrane is thrown into several folds called junctional folds, which contains nicotinic type of ACh receptors at their crests.
Mechanism of the Neuromuscular Transmission:
Arrival of motor neuron action potential, depolarizes the membrane of terminal buttons → Activation and opening of voltage-gated calcium channels, leads to calcium influx in axon terminal → Movement of ACh vesicles to inner surface of presynaptic membrane → Vesicles fuse to the membrane and release ACh into synaptic cleft by exocytosis → ACh diffuses across synaptic cleft and bind to the ACh receptors on the motor end plate → Binding of ACh causes Na+ influx and K+ efflux, producing a local depolarization of the motor end plate known as end plate potential (EPP) → EPP is non-progressive, but when critical level of -60 is reached, generates action potential → Spread of action potential in both the direction along muscle fiber to the T-tubules → Excitation-contraction coupling occurs, which leads to muscle contraction.
Miniature End Plate Potential (MEPP):
Even at rest the motor neuron has spontaneously occurring potentials of minute amplitude (0.4 mV) lasting for a few milliseconds due to ACh release randomly from the nerve terminal. This is called miniature endplate potential.
Drugs Acting at Neuromuscular Junction:
1. Neuromuscular Blockers:
i. Botulinum Toxin:
It blocks neuromuscular transmission by preventing the release of ACh from the terminal buttons of nerve ending. This toxin is derived from the bacteria Clostridium botulinum.
Prevents neuromuscular transmission by competitive inhibition. It binds to the ACh receptors on postsynaptic membrane and hence ACh released fails to bind with the receptor and so no endplate potential is developed.
Found in the venom of snakes, blocks the neuromuscular transmission by binding to ACh receptors.
iv. Succinylcholine and Carbamylcholine:
It blocks the neuromuscular transmission by keeping the muscle in depolarized state. It acts like ACh and depolarize the postsynaptic membrane, but these are not destroyed by ACh esterase and hence muscle remains in depolarized state for long time.
2. Neuromuscular Stimulators:
i. Drugs having ACh like Action:
Carbachol and nicotine both are not destroyed or destroyed little by ACh esterase. So they cause muscle spasm due to repeated stimulation and continuous action of muscle.
ii. Drugs that Inactivate ACh Esterase:
Neostigmine and physostigmine stimulate neuromuscular junction by inactivating acetyl cholinesterase.
Disorders at Neuromuscular Junction:
1. Myasthenia Gravis:
It is an autoimmune disorder affecting the neuromuscular junction. It occurs in about 1 in every 20,000 persons. In this disease antibodies are produced against the ACh receptors on motor endplate and they are destroyed. Hence, ACh released is unable to bind with the ACh receptor to produce adequate EPP to excite the muscle fiber.
So, the transmission of signals from the nerve fiber to muscle does not occur, leading to paralysis of the involved muscle. If the disease is intense, patient dies due to paralysis of respiratory muscle. It is treated by neostigmine, physostigmine and di-isopropyl fluorophosphates (DIFP).
2. Lambert-Eaton Myasthenic Syndrome:
It is a presynaptic disorder of neuromuscular junction, where autoantibodies are produced against voltage- gated Ca++ channels. This leads to decrease in calcium influx in terminal knob, and decreases the release of ACh. Upper limb muscular weakness is seen in this disease.