Neuromuscular Transmission

Neuromuscular junctions are specific chemical synapses. The synapses between the axons of motor neurons and skeletal muscle fibers (also known as "motor end-plates") have been the first synapses studied. They possess all common characteristics of the CNS synapses.

Structure
Near the neuromuscular junction the motor nerve loses its myelin sheath and divides into fine terminal branches that lie in synaptic troughs on the surface of the muscle cells. The plasma membrane of the muscle cell lining the trough is thrown into numerous junctional folds. The axon terminals contain many synaptic vesicles (~40 nm diameter) containing acetylcholine. Acetylcholine receptors are concentrated near the mouths of the junctional folds. Acetylcholinesterase is evenly distributed on the external surface of the postsynaptic membrane.

Neuromuscular junctions are designed for a rapid transmission, by having the following characteristics:


 * 1) Large myelinated motor axon
 * 2) Large active zone of the axon terminal
 * 3) Numerous synaptic vesicles held ready to release their content precisely opposite the postsynaptic receptors
 * 4) Narrow synaptic cleft (50nm)
 * 5) Ligand-gated channels (fast → response = < 1ms)
 * 6) Acetylcholinesterase in the cleft to terminate the transmission and allow the next one as soon as possible

Function
The steps that take place when the action potential is conducted to the muscle fiber are:


 * 1) The depolarization caused by an action potential transiently opens voltage-gated Ca2+ channels and increases the calcium conductance. Ca2+ flows down its electrochemical potential gradient into the axon terminal at a high rate
 * 2) The increase of free Ca2+ concentration is short-lived, because Ca2+-binding proteins and Ca2+ pumps (e.g. Na/Ca anti-porter) rapidly take up and remove the Ca2+, respectively. In this way the terminal is ready to transmit another signal in a very short time.
 * 3) The influx of Ca2+ triggers an interaction of contractile proteins (synapsin I = actin-like protein), attached to the presynaptic membrane, with synaptic vesicles. Vesicles fuse with the presynaptic membrane and discharge their contents into the synaptic cleft (exocytosis).
 * 4) The exocytosis is restricted to specialized regions known as active zones (or release sites), exactly opposite the receptors on the postsynaptic cell. The membrane of the discharged synaptic vesicles is subsequently retrieved from the presynaptic plasma membrane by endocytosis.
 * 5) An axon terminal at a neuromuscular junction typically releases a few hundred of its many thousands of synaptic vesicles in a response to a single action potential.
 * 6) The time required for calcium channels to open in response to depolarization is the major component of synaptic delay.
 * 7) The conversion of the chemical signal into an electrical signal is achieved by ligand-gated ion channels in the postsynaptic membrane. When transmitter binds to the receptor proteins, they change their conformation - open the ion channel → membrane potential is altered. If the shift of membrane potential is large enough, it causes the voltage-gated channels to open → action potential is triggered.

Unlike voltage-gated ion channels, the ligand-gated ion channels are relatively insensitive to the membrane potential. They cannot by themselves produce an all-or-non, self-amplifying excitation. Instead they produce an electrical change that is graded according to the intensity and duration of the external chemical signal, according to how much transmitter is released into the synaptic cleft and how long it stays there. This feature is important for the integration properties of the signal by neurons.

Postsynaptic ligand-gated channels have enzyme-like specificity for a particular ligand → they respond only to one neurotransmitter (the one released from the presynaptic terminal), with other transmitters having no effect. In their role as channels, they are characterized by different ion selectivity (to K+, Cl-, nonselective to cations but exclude anions) → the ion selectivity determines the character of the postsynaptic response.

The channels in the skeletal muscle cell membrane gated by acetylcholine (acetylcholine receptors) have several discrete alternative conformations. Upon binding acetylcholine the channel jumps from closed to an open state and then stays open, with the ligand bound, for a randomly variable length of time (average about 1ms, depending on temperature and the species). In the open conformation the channel is indiscriminately permeable to small cations including Na+, K+, and Ca2+, but impermeable to anions. Since there is little selectivity among these cations, their relative contributions to the current through the channel depend chiefly on their concentrations and on the electrochemical driving forces:


 * If the muscle cell membrane is at its resting potential, the net driving force for K+ is near zero, because the voltage gradient (negative inside) nearly balances the K+ concentration gradient.
 * For Na+, the voltage gradient and the concentration gradient both act in the same direction to drive Na+ into the cell. Similarly some Ca2+ ions contribute to the total inward current.

In order for the post-synaptic excitation to be accurately controlled by the pattern of signals sent from the presynaptic terminal, it must be switched off very rapidly when the presynaptic cell falls quiet. This is achieved by the removal of the acetylcholine from the synaptic cleft and it takes a few hundred microseconds:


 * 1) Acetylcholine disperses by diffusion
 * 2) Acetylcholine is hydrolyzed by acetylcholinesterase to acetate and choline