Transmission across the majority of synapses in the nervous system is one-way and occurs through the release of chemical neu-rotransmitters from presynaptic axon endings. These presynaptic endings, called terminal boutons (bouton = button) because of their swollen appearance, are separated from the postsynaptic cell by a synaptic cleft so narrow (about 10 nm) that it can be seen clearly only with an electron microscope (fig. 7.20).
Neurotransmitter molecules within the presynaptic neuron endings are contained within many small, membrane-enclosed synaptic vesicles. In order for the neurotransmitter within these vesicles to be released into the synaptic cleft, the vesicle membrane must fuse with the axon membrane in the process of exo-cytosis (chapter 3). The neurotransmitter is released in multiples of the amount contained in one vesicle, and the number of vesicles that undergo exocytosis depends on the frequency of action potentials produced at the presynaptic axon ending. Therefore,
Terminal — bouton of axon
Terminal — bouton of axon
Postsynaptic cell (skeletal muscle)
■ Figure 7.20 An electron micrograph of a chemical synapse. This synapse between the axon of a somatic motor neuron and a skeletal muscle cell shows the synaptic vesicles at the end of the axon and the synaptic cleft. The synaptic vesicles contain the neurotransmitter chemical.
when stimulation of the presynaptic axon is increased, more of its vesicles will release their neurotransmitters to more greatly affect the postsynaptic cell.
Action potentials that arrive at the end of the axon trigger the release of neurotransmitter quite rapidly. The release is rapid because many synaptic vesicles are already "docked" at the correct areas of the presynaptic membrane before the arrival of the action potentials. At these docking sites, the vesicles are attached by proteins to form a fusion complex associated with the presyn-aptic membrane. The fusion complex attaches the vesicle to the docking site, but actual fusion of the vesicle membrane and the axon membrane is prevented until the arrival of action potentials.
Voltage-regulated calcium (Ca2+) channels are located in the axon terminal adjacent to the docking sites. The arrival of action potentials at the axon terminal opens these voltage-regulated calcium channels, and it is the inward diffusion of Ca2+ that triggers
Fox: Human Physiology, I 7. The Nervous System: I Text I I © The McGraw-Hill
Eighth Edition Neurons and Synapses Companies, 2003
The Nervous System: Neurons and Synapses 169
activates Protein kinase Calmodulin (inactive)
Synaptic r vesicles
Protein kinase (active)
phosphorylates synapsin proteins iV
Fusion and exocytosis
■ Figure 7.21 The release of neurotransmitter. Action potentials, by opening Ca2+ channels, stimulate the fusion of docked synaptic vesicles with the cell membrane of the axon terminals. This leads to exocytosis and the release of neurotransmitter. The activation of protein kinase by Ca2+ may also contribute to this process.
the rapid fusion of the synaptic vesicle with the axon membrane and the release of neurotransmitter through exocytosis (fig. 7.21).
In addition, Ca2+ diffusing into the axon terminal activates a regulatory protein within the cytoplasm known as calmodulin, which in turn activates an enzyme called protein kinase. This enzyme phosphorylates (adds a phosphate group to) specific proteins known as synapsins in the membrane of the synaptic vesicle. This action may aid the fusion of synaptic vesicles with the plasma membrane. The Ca2+-calmodulin-protein kinase regulatory mechanism is also important in the action of some hormones, and is therefore discussed in more detail in chapter 11.
Tetanus toxin and botulinum toxin are bacterial products that cause paralysis by preventing neurotransmission. These neurotoxins function as proteases (protein-digesting enzymes), digesting particular components of the fusion complex and thereby inhibiting the exocytosis of synaptic vesicles and preventing the release of neurotransmitter. Botulinum toxin prevents the release of ACh, causing flaccid paralysis; tetanus toxin blocks inhibitory synapses (discussed later), causing spastic paralysis.
Once the neurotransmitter molecules have been released from the presynaptic axon terminals, they diffuse rapidly across the synaptic cleft and reach the membrane of the postsynaptic cell. The neurotransmitters then bind to specific receptor proteins that are part of the postsynaptic membrane. Receptor proteins have high specificity for their neurotransmitter, which is the ligand of the receptor protein. The term ligand in this case refers to a smaller molecule (the neurotransmitter) that binds to and forms a complex with a larger protein molecule (the receptor). Binding of the neurotransmitter ligand to its receptor protein causes ion channels to open in the postsynaptic membrane. The gates that regulate these channels, therefore, can be called chemically regulated (or ligand-regulated) gates because they open in response to the binding of a chemical ligand to its receptor in the postsynaptic plasma membrane.
Note that two broad categories of gated ion channels have been described: voltage-regulated and chemically regulated. Voltage-regulated channels are found primarily in the axons; chemically regulated channels are found in the postsynaptic membrane. Voltage-regulated channels open in response to depolarization; chemically regulated channels open in response to the binding of postsynaptic receptor proteins to their neurotrans-mitter ligands.
The chemically regulated channels are opened by a number of different mechanisms, and the effects of opening these channels vary. Opening of ion channels often produces a depolarization— the inside of the postsynaptic membrane becomes less negative. This depolarization is called an excitatory postsynaptic potential (EPSP) because the membrane potential moves toward threshold. In other cases, a hyperpolarization occurs—the inside of the post-synaptic membrane becomes more negative. This hyperpolarization is called an inhibitory postsynaptic potential (IPSP) because the membrane potential moves farther from threshold. The mechanisms by which EPSPs and IPSPs are produced will be described in the sections that deal with different types of neurotransmitters.
Excitatory postsynaptic potentials, as their name implies, stimulate the postsynaptic cell to produce action potentials, and inhibitory postsynaptic potentials antagonize this effect. In synapses between the axon of one neuron and the dendrites of another, the EPSPs and IPSPs are produced at the dendrites and must propagate to the initial segment of the axon to influence action potential production (fig. 7.22). The total depolarization
■ Figure 7.22 The functional specialization of different regions in a multipolar neuron. Integration of input (EPSPs and IPSPs) generally occurs in the dendrites and cell body, with the axon serving to conduct action potentials.
produced by the summation of EPSPs at the initial segment of the axon will determine whether the axon will fire action potentials, and the frequency with which it fires action potentials. Once the first action potentials are produced, they will regenerate themselves along the axon as previously described.
In summary, the following sequence of events occurs:
1. An excitatory neurotransmitter produces a depolarization. This occurs when the neurotransmitter binds to its receptor and causes the opening of chemically regulated ion channels in the postsynaptic membrane. (An inhibitory neurotransmitter has the opposite effect—it causes a hyperpolarization.)
2. The depolarization causes the opening of voltage-regulated ion channels. This occurs if the depolarization reaches threshold.
3. Opening of voltage-regulated channels produces action potentials. This occurs in the first region of the postsynaptic membrane that contains voltage-regulated channels. In neurons, this is the initial segment of the axon.
4. The action potential is regenerated along the axon or muscle cell. An action potential in one region serves as the depolarization stimulus for the next region.
Test Yourself Before You Continue
1. Describe the structure, locations, and functions of gap junctions.
2. Describe the location of neurotransmitters within an axon and explain the relationship between presynaptic axon activity and the amount of neurotransmitters released.
3. Describe the sequence of events by which action potentials stimulate the release of neurotransmitters from presynaptic axons.
4. Distinguish between voltage-regulated and chemically regulated ion channels.
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