More than 50 chemical substances have been proved or postulated to function as synaptic transmitters. Many of them are listed in Tables 1 and 2, which provide two groups of synaptic transmitters. One group comprises small-molecule, rapidly acting transmitters. The other is made up of a large number of neuropeptides of much larger molecular size that usually act much more slowly.
Table1. Small-Molecule, Rapidly Acting Transmitters
Table2. Neuropeptide, Slowly Acting Transmitters or Growth Factors
The small-molecule, rapidly acting transmitters cause most acute responses of the nervous system, such as transmission of sensory signals to the brain and of motor signals back to the muscles. The neuropeptides, in contrast, usually cause more prolonged actions, such as long-term changes in numbers of neuronal receptors, long-term opening or closure of certain ion channels, and possibly even long-term changes in numbers of synapses or sizes of synapses.
Small-Molecule, Rapidly Acting Transmitters
In most cases, the small-molecule types of transmitters are synthesized in the cytosol of the presynaptic terminal and are absorbed by means of active transport into the many transmitter vesicles in the terminal. Then, each time an action potential reaches the presynaptic terminal, a few vesicles at a time release their transmitter into the synaptic cleft. This action usually occurs within a millisecond or less by the mechanism described earlier. The subsequent action of the small-molecule transmitter on the membrane receptors of the postsynaptic neuron usually also occurs within another millisecond or less. Most often the effect is to increase or decrease conductance through ion channels; an example is to increase sodium conductance, which causes excitation, or to increase potassium or chloride conductance, which causes inhibition.
Recycling of the Small-Molecule Types of Vesicles. Vesicles that store and release small-molecule transmitters are continually recycled and used over and over again. After they fuse with the synaptic membrane and open to release their transmitter substance, the vesicle membrane at first simply becomes part of the synaptic membrane. However, within seconds to minutes, the vesicle portion of the membrane invaginates back to the inside of the presynaptic terminal and pinches off to form a new vesicle. The new vesicular membrane still contains appropriate enzyme proteins or transport proteins required for synthesizing and/or concentrating new transmitter substance inside the vesicle.
Acetylcholine is a typical small-molecule transmitter that obeys the principles of synthesis and release stated earlier. This transmitter substance is synthesized in the presynaptic terminal from acetyl coenzyme A and choline in the presence of the enzyme choline acetyltransferase. It is then transported into its specific vesicles. When the vesicles later release the acetylcholine into the synaptic cleft during synaptic neuronal signal transmission, the acetylcholine is rapidly split again to acetate and choline by the enzyme cholinesterase, which is present in the proteoglycan reticulum that fills the space of the synaptic cleft. Then once again, inside the presynaptic terminal, the vesicles are recycled, and choline is actively trans ported back into the terminal to be used again for synthesis of new acetylcholine.
Characteristics of Some Important Small-Molecule Transmitters. Acetylcholine is secreted by neurons in many areas of the nervous system but specifically by (1) the terminals of the large pyramidal cells from the motor cortex, (2) several different types of neurons in the basal ganglia, (3) the motor neurons that innervate the skeletal muscles, (4) the preganglionic neurons of the autonomic nervous system, (5) the postganglionic neurons of the parasympathetic nervous system, and (6) some of the postganglionic neurons of the sympathetic nervous system. In most instances, acetylcholine has an excitatory effect; however, it is known to have inhibitory effects at some peripheral parasympathetic nerve endings, such as inhibition of the heart by the vagus nerves.
Norepinephrine is secreted by the terminals of many neurons whose cell bodies are located in the brain stem and hypothalamus. Specifically, norepinephrine-secreting neurons located in the locus ceruleus in the pons send nerve fibers to widespread areas of the brain to help control overall activity and mood of the mind, such as increasing the level of wakefulness. In most of these areas, norepinephrine probably activates excitatory receptors, but in a few areas, it activates inhibitory receptors instead. Norepinephrine is also secreted by most postganglionic neurons of the sympathetic nervous system, where it excites some organs but inhibits others.
Dopamine is secreted by neurons that originate in the substantia nigra. The termination of these neurons is mainly in the striatal region of the basal ganglia. The effect of dopamine is usually inhibition.
Glycine is secreted mainly at synapses in the spinal cord. It is believed to always act as an inhibitory transmitter
GABA (gamma-aminobutyric acid) is secreted by nerve terminals in the spinal cord, cerebellum, basal ganglia, and many areas of the cortex. It is believed to always cause inhibition.
Glutamate is secreted by the presynaptic terminals in many of the sensory pathways entering the central nervous system, as well as in many areas of the cerebral cortex. It probably always causes excitation.
Serotonin is secreted by nuclei that originate in the median raphe of the brain stem and project to many brain and spinal cord areas, especially to the dorsal horns of the spinal cord and to the hypothalamus. Serotonin acts as an inhibitor of pain pathways in the cord, and an inhibitor action in the higher regions of the nervous system is believed to help control the mood of the person, perhaps even to cause sleep.
Nitric oxide is especially secreted by nerve terminals in areas of the brain responsible for long-term behavior and memory. Therefore, this transmitter system might in the future explain some behavior and memory functions that thus far have defied understanding. Nitric oxide is different from other small-molecule transmitters in its mechanism of formation in the presynaptic terminal and in its actions on the postsynaptic neuron. It is not preformed and stored in vesicles in the presynaptic terminal as are other transmitters. Instead, it is synthesized almost instantly as needed and then diffuses out of the presynaptic terminals over a period of seconds rather than being released in vesicular packets. Next, it diffuses into postsynaptic neurons nearby. In the postsynaptic neuron, it usually does not greatly alter the membrane potential but instead changes intracellular metabolic functions that modify neuronal excitability for seconds, minutes, or perhaps even longer.
Neuropeptides
Neuropeptides are synthesized differently and have actions that are usually slow and in other ways quite different from those of the small-molecule transmitters. The neuropeptides are not synthesized in the cytosol of the presynaptic terminals. Instead, they are synthesized as integral parts of large-protein molecules by ribosomes in the neuronal cell body.
The protein molecules then enter the spaces inside the endoplasmic reticulum of the cell body and subsequently inside the Golgi apparatus, where two changes occur: First, the neuropeptide-forming protein is enzymatically split into smaller fragments, some of which are either the neuropeptide itself or a precursor of it. Second, the Golgi apparatus packages the neuropeptide into minute transmitter vesicles that are released into the cytoplasm. Then the transmitter vesicles are transported all the way to the tips of the nerve fibers by axonal streaming of the axon cytoplasm, traveling at the slow rate of only a few centimeters per day. Finally, these vesicles release their transmitter at the neuronal terminals in response to action potentials in the same manner as for small-molecule transmitters. However, the vesicle is autolyzed and is not reused.
Because of this laborious method of forming the neuropeptides, much smaller quantities of neuropeptides than of the small-molecule transmitters are usually released. This difference is partly compensated for by the fact that the neuropeptides are generally a thousand or more times as potent as the small-molecule transmitters. Another important characteristic of the neuropeptides is that they often cause much more prolonged actions. Some of these actions include prolonged closure of calcium channels, prolonged changes in the metabolic machinery of cells, prolonged changes in activation or deactivation of specific genes in the cell nucleus, and/or prolonged alterations in numbers of excitatory or inhibitory receptors. Some of these effects last for days, but others last perhaps for months or years. Our knowledge of the functions of the neuropeptides is only beginning to develop.
