Chapter 53 – Synapses and the Neuromuscular Junction

Abstract

Chemical synapse, in which the signal is relayed by means of a chemical messenger called a neurotransmitter. Arrival of an action potential triggers neurotransmitter release into the synaptic cleft, a narrow (20–50‑nm) gap between the pre- and post-synaptic membranes, which excites or inhibits the postsynaptic cell. An example of a chemical synapse is the neuromuscular junction (NMJ): the terminal bouton of an α-motor neuron forms a synapse with the motor end plate of a skeletal muscle cell. Action potential transmissions at chemical synapses are typically unidirectional: the signal can only be transmitted from pre- to post-synaptic cells. Transmission of an action potential across a chemical synapse is associated with a synaptic delay, as it takes time for each of the processes of neurotransmitter release, diffusion and combination with postsynaptic receptors to occur.

Chapter 53 Synapses and the Neuromuscular Junction

What is a synapse?

A synapse is the functional point of contact between two excitable cells, across which a signal can be transmitted. There are two types of synapse:

Chemical synapse, in which the signal is relayed by means of a chemical messenger called a neurotransmitter. Arrival of an action potential triggers neurotransmitter release into the synaptic cleft, a narrow (20–50‑nm) gap between the pre- and post-synaptic membranes, which excites or inhibits the postsynaptic cell. An example of a chemical synapse is the neuromuscular junction (NMJ): the terminal bouton of an α-motor neuron forms a synapse with the motor end plate of a skeletal muscle cell. Action potential transmissions at chemical synapses are typically unidirectional: the signal can only be transmitted from pre- to post-synaptic cells. Transmission of an action potential across a chemical synapse is associated with a synaptic delay, as it takes time for each of the processes of neurotransmitter release, diffusion and combination with postsynaptic receptors to occur.
Electrical synapse, in which the pre- and post-synaptic cells are electrically connected by gap junctions that allow electric current to pass; an action potential in the presynaptic cell induces a local current in the postsynaptic cell, which triggers an action potential. Signals are transferred from neuron to target cell without a synaptic delay, and therefore this occurs more rapidly than when the cells are connected by a chemical synapse. This is exemplified by cardiac muscle, where gap junctions are essential for the rapid conduction of action potentials (see Chapter 57). Electrical synapses are bidirectional: the signal can be transmitted from pre- to post-synaptic cells, or vice versa.

What are neurotransmitters?

A neurotransmitter is a substance released by a neuron at a synapse, which then acts upon the postsynaptic cell. Neurotransmitters are classified as:

Small molecules, of which there are three main classes:
1. – Amines: acetylcholine (ACh), histamine, serotonin (5-HT), catecholamines (noradrenaline, adrenaline, dopamine);
2. – Amino acids: γ-amino butyric acid (GABA), glycine, glutamate;
3. – Purines: ATP, adenosine.
Large molecules; over 50 neuroactive peptides are known, including:
1. – Opioids: β-endorphin, enkephalins;
2. – Tachykinins: substance P, neurokinins;
3. – Secretins;
4. – Somatostatins.

Most neurotransmitters exert excitatory effects on the target cell, which may result in the triggering of an action potential (if the target cell is a nerve or muscle) or secretion (if the target cell is a gland). The most widespread excitatory neurotransmitter is glutamate, which is present in over 90% of synapses in the brain. Some neurotransmitters are inhibitory, causing either increased K⁺ conductance resulting in hyperpolarisation or increased Cl‾ conductance at the postsynaptic membrane, thereby reducing the likelihood of an action potential being generated. GABA, the second most prevalent neurotransmitter in the brain, is the major inhibitory neurotransmitter. Glycine is an inhibitory neurotransmitter that is particularly widespread in the spinal cord and brainstem.

Occasionally, neurotransmitters have an excitatory effect at one synapse whilst having an inhibitory effect at another. For example, ACh is an excitatory neurotransmitter at the nicotinic receptors of the NMJ, but it produces an inhibitory response at the muscarinic M₂ receptors of the heart.

How are neurotransmitters released into the synaptic cleft?

Neurotransmitters are stored in packets called vesicles, which are docked at the active zone of the presynaptic membrane. When the action potential propagates down the axon and into the terminal bouton (Figure 53.1a), a well-defined sequence of events occurs:

Increase in presynaptic Ca²⁺ concentration. Depolarisation results in the opening of voltage-gated Ca²⁺ channels (N-type). Ca²⁺ diffuses down its electrochemical gradient from the extracellular fluid (ECF) to the cell interior (Figure 53.1b).
Exocytosis. Periodically, vesicles in the active zone spontaneously fuse with the presynaptic membrane, releasing their neurotransmitter contents into the synaptic cleft. Axonal Ca²⁺ binds to a vesicular membrane protein called synaptotagmin, which, in conjunction with proteins known as SNAREs,¹ triggers 50–100 vesicles to undergo exocytosis. Thus, a very large number of neurotransmitter molecules are released into the synaptic cleft following an action potential.
Diffusion across the synaptic cleft. The neurotransmitters diffuse down their concentration gradient, travelling the short distance to the postsynaptic membrane.
Binding to postsynaptic receptors. Neurotransmitters that reach the postsynaptic membrane bind to specific receptors, resulting in excitation or inhibition of the membrane (Figure 53.1c).

Figure 53.1 The mechanism of a chemical synapse.

What is the difference between an ionotropic and a metabotropic receptor?

At the postsynaptic membrane, neurotransmitters encounter two types of receptor:

Ionotropic receptors are ligand-gated postsynaptic ion channels. Binding of a neurotransmitter and the resulting alteration of their conformation directly results in ion channel opening.
Metabotropic receptors. Binding of a neurotransmitter also causes the receptor to change its conformation. However, metabotropic receptors are indirectly linked to membrane ion channels through intermediate intracellular chemical messengers, usually involving a G protein. An important example of a metabotropic synapse is the muscarinic (M₂) ACh receptor of the pacemaker cells in the heart (see Chapter 57).

What is the mechanism for ionotropic receptor signalling?

Ionotropic signalling may produce either an excitatory postsynaptic potential (EPSP) or an inhibitory postsynaptic potential (IPSP) depending on the flow of ions at the postsynaptic ion channel:

In an EPSP, binding of neurotransmitter at the postsynaptic membrane opens non-specific cation channels.
1. – Na⁺ and K⁺ diffuse along their electrochemical gradients: Na⁺ flows into the postsynaptic cell from the synaptic cleft, whilst K⁺ diffuses out of the cell. Overall, Na⁺ influx is greater than K⁺ efflux; the net intracellular movement of positively charged ions causes a depolarisation of the postsynaptic membrane – the EPSP.
2. – There is usually an excess of postsynaptic ion channels; the size of the EPSP is therefore dependent on the number of neurotransmitter vesicles released:
  1. ▪ The spontaneous exocytosis of a single vesicle of neurotransmitter results in a miniature 0.5‑mV depolarisation. This depolarisation is not large enough to reach threshold potential and the EPSP will fade back to the resting membrane potential (RMP).
  2. ▪ Following an action potential, a large number of neurotransmitters are released into the synaptic cleft. The depolarising effect of each vesicle’s contents at the postsynaptic membrane is additive; to exceed threshold potential and generate an action potential at the postsynaptic cell, many vesicles must be released simultaneously (Figure 53.2a).
In an IPSP, the postsynaptic membrane contains either ligand-gated K⁺ or Cl‾ channels.
1. – K⁺-mediated IPSPs: binding of neurotransmitter opens specific K⁺ channels. K⁺ ions diffuse along their electrochemical gradient from the postsynaptic cell to the synaptic cleft. The efflux of positively charged ions hyperpolarises the cell membrane, making it more difficult to reach threshold potential (Figure 53.2b).
2. – Cl‾-mediated IPSP: binding of neurotransmitter opens Cl‾ channels. The resulting intracellular movement of Cl‾ ions usually makes little difference to the postsynaptic membrane potential, as the Nernst potential of Cl‾ (–70 mV) is approximately the same voltage as the RMP. However, to reach threshold, an excitatory signal must trigger sufficient Na⁺ influx to exceed the combined effects of Cl‾ influx and K⁺ efflux, making it much more difficult to depolarise the cell membrane; this is known as the ‘chloride clamp’.