Chemical Synapses

In chemical synapses, there is a gap between the presynaptic cell membrane and the postsynaptic cell membrane, known as the synaptic cleft. Information is transmitted across the synaptic cleft via a neurotransmitter, a substance that is released from the presynaptic terminal and binds to receptors on the postsynaptic terminal.

The following sequence of events occurs at chemical synapses: An action potential in the presynaptic cell causes Ca²⁺ channels to open. An influx of Ca²⁺ into the presynaptic terminal causes the neurotransmitter, which is stored in synaptic vesicles, to be released by exocytosis. The neurotransmitter diffuses across the synaptic cleft, binds to receptors on the postsynaptic membrane, and produces a change in membrane potential on the postsynaptic cell.

The change in membrane potential on the postsynaptic cell membrane can be either excitatory or inhibitory, depending on the nature of the neurotransmitter released from the presynaptic nerve terminal. If the neurotransmitter is excitatory, it causes depolarization of the postsynaptic cell; if the neurotransmitter is inhibitory, it causes hyperpolarization of the postsynaptic cell.

In contrast to electrical synapses, neurotransmission across chemical synapses is unidirectional (from presynaptic cell to postsynaptic cell). The synaptic delay is the time required for the multiple steps in chemical neurotransmission to occur.

Neuromuscular Junction - Example of a Chemical Synapse

Motor Units

Motoneurons are the nerves that innervate muscle fibers. A motor unit comprises a single motoneuron and the muscle fibers it innervates. Motor units vary considerably in size: A single motoneuron may activate a few muscle fibers or thousands of muscle fibers. Predictably, small motor units are involved in fine motor activities (e.g., facial expressions), and large motor units are involved in gross muscular activities (e.g., quadriceps muscles used in running).

Sequence of Events at the Neuromuscular Junction

The synapse between a motoneuron and a muscle fiber is called the neuromuscular junction. An action potential in the motoneuron produces an action potential in the muscle fibers it innervates by the following sequence of events:

1. Action potentials are propagated down the motoneuron. Local currents depolarize each adjacent region to threshold. Finally, the presynaptic terminal is depolarized, and this depolarization causes voltage-gated Ca²⁺ channels in the presynaptic membrane to open.

2. When these Ca²⁺ channels open, the Ca²⁺ permeability of the presynaptic terminal increases, and Ca²⁺ flows into the terminal down its electrochemical gradient.

3. Ca²⁺ uptake into the terminal causes release of the neurotransmitter acetylcholine (ACh), which has been previously synthesized and stored in synaptic vesicles. To release ACh, the synaptic vesicles fuse with the plasma membrane and empty their contents into the synaptic cleft by exocytosis.

ACh is formed from acetyl coenzyme A (acetyl CoA) and choline by the action of the enzyme choline acetyltransferase. ACh is stored in vesicles with ATP and proteoglycan for subsequent release. On stimulation, the entire content of a synaptic vesicle is released into the synaptic cleft. The smallest possible amount of ACh that can be released is the content of one synaptic vesicle (one quantum), and for this reason, the release of ACh is said to be quantal. 

4. ACh diffuses across the synaptic cleft to the postsynaptic membrane. This specialized region of the muscle fiber is called the motor end plate, which contains nicotinic receptors for ACh. ACh binds to the α subunits of the nicotinic receptor and causes a conformational change. It is important to note that the nicotinic receptor for ACh is an example of a ligand-gated ion channel: It also is an Na⁺ and K⁺channel. When the conformational change occurs, the central core of the channel opens, and the permeability of the motor end plate to both Na⁺ and K⁺ increases.

5. When these channels open, both Na⁺ and K⁺ flow down their respective electrochemical gradients, Na⁺ moving into the end plate and K⁺ moving out, each ion attempting to drive the motor end plate potential to its equilibrium potential. Indeed, if there were no other ion channels in the motor end plate, the end plate would depolarize to a value about halfway between the equilibrium potentials for Na⁺ and K⁺, or approximately 0 mV. (In this case, zero is not a "magic number" - it simply happens to be the value about halfway between the two equilibrium potentials.) In practice, however, because other ion channels that influence membrane potential are present in the end plate, the motor end plate only depolarizes to about -50 mV, which is the end plate potential (EPP). The EPP is not an action potential but is simply a local depolarization of the specialized motor end plate.

The content of a single synaptic vesicle produces the smallest possible change in membrane potential of the motor end plate, the miniature end plate potential (MEPP). MEPPs summate to produce the full-fledged EPP. The spontaneous appearance of MEPPs proves the quantal nature of ACh release at the neuromuscular junction.

Each MEPP, which represents the content of one synaptic vesicle, depolarizes the motor end plate by about 0.4 mV. An EPP is a multiple of these 0.4 mV units of depolarization. How many such quanta are required to depolarize the motor end plate to the EPP? Because the motor end plate must be depolarized from its resting potential of -90 mV to the threshold potential of -50 mV, it must, therefore, depolarize by 40 mV. Depolarization by 40 mV requires 100 quanta (because each quantum or vesicle depolarizes the motor end plate by 0.4 mV).

6. Depolarization of the motor end plate (the EPP) then spreads by local currents to adjacent muscle fibers, which are depolarized to threshold and fire action potentials. Although the motor end plate itself cannot fire action potentials, it depolarizes sufficiently to initiate the process in the neighboring "regular" muscle cells. Action potentials are propagated down the muscle fiber by a continuation of this process.

7. The EPP at the motor end plate is terminated when ACh is degraded to choline and acetate by acetylcholinesterase (AChE) on the motor end plate. Approximately 50% of the choline is returned to the presynaptic terminal by Na⁺-choline cotransport, to be used again in the synthesis of new ACh.

Agents That Alter Neuromuscular Function

Several agents interfere with normal activity at the neuromuscular junction, and their mechanisms of action can be readily understood by considering the steps involved in neuromuscular transmission.

♦ Botulinus toxin blocks the release of ACh from presynaptic terminals, causing total blockade of neuromuscular transmission, paralysis of skeletal muscle, and, eventually, death from respiratory failure.

♦ Curare competes with ACh for the nicotinic receptors on the motor end plate, decreasing the size of the EPP. When administered in maximal doses, curare causes paralysis and death. D-Tubocurarine, a form of curare, is used therapeutically to cause relaxation of skeletal muscle during anesthesia. A related substance, α-bungarotoxin, binds irreversibly to ACh receptors. Binding of radioactive α-bungarotoxin has provided an experimental tool for measuring the density of ACh receptors on the motor end plate.

♦ AChE inhibitors (anticholinesterases) such as neostigmine prevent degradation of ACh in the synaptic cleft, and they prolong and enhance the action of ACh at the motor end plate. AChE inhibitors can be used in the treatment of myasthenia gravis, a disease characterized by skeletal muscle weakness and fatigability, in which ACh receptors are blocked by antibodies.

♦ Hemicholinium blocks choline reuptake into presynaptic terminals, thus depleting choline stores from the motoneuron terminal and decreasing the synthesis of ACh.