Regardless of the type of chemical mediator involved, several common steps comprise the process of transmission at a chemical synapse. The first steps are the synthesis of the neurotransmitter usually within the nerve terminal and its storage within synaptic vesicles. This is followed by release of the chemical into the synaptic cleft in response to nerve impulses. The secreted neurotransmitter can then act on receptors on the membrane of the postsynaptic neuron, effector organ (eg, muscle or gland), or even on the presynaptic nerve terminal. The final steps in the process lead to termination of the actions of the neurotransmitter and include diffusion away from the synaptic cleft, reuptake into the nerve terminal, and enzymatic degradation. All of these processes, plus the events in the post synaptic neuron, are regulated by many physiologic factors and can be altered by drugs. Therefore, pharmacologists (in theory) should be able to develop drugs that regulate not only somatic and visceral motor activity but also emotions, behavior, and all the other complex functions of the brain. Some chemicals released by neurons have little or no direct effects on their own but can modify the effects of neurotransmitters. These chemicals are called neuromodulators.
CHEMISTRY OF TRANSMITTERS
Many neurotransmitters and the enzymes involved in their synthesis and catabolism have been localized in nerve endings by immunohistochemistry, a technique in which antibodies to a given substance are labeled and applied to the brain and other tissues. The antibodies bind to the substance, and the location of the substance is then determined by locating the label with the light or electron microscope. In situ hybridization histochemistry, which permits localization of the mRNAs for particular synthesizing enzymes or receptors, has also been a valuable tool.
There are two main classes of chemical substances that serve as neurotransmitters and neuromodulators: small molecule transmitters and large-molecule transmitters. Small molecule transmitters include amino acids (eg, glutamate, γ-aminobutyric acid [GABA], and glycine), acetylcholine, monoamines (eg, norepinephrine, epinephrine, dopamine, and serotonin), and adenosine triphosphate (ATP). Large molecule transmitters include neuropeptides such as sub stance P, enkephalin, vasopressin, and a host of others. In general, neuropeptides are co-localized with one of the small molecule neurotransmitters (Table1).
Table1. Examples of co-localization of small molecule transmitters with neuropeptides.
Figure 1 shows the biosynthesis of some common small-molecule transmitters released by neurons in the central nervous system (CNS) or peripheral nervous system. Figure2 shows the location of major groups of neurons that contain norepinephrine, epinephrine, dopamine, and acetyl choline. These are some of the major central neurotransmitter and neuromodulatory systems.
Fig1. Biosynthesis of some common small-molecule neurotransmitters. A) Glutamate is synthesized in the Krebs cycle by the conversion of α-ketoglutarate to the amino acid via the enzyme γ-aminobutyric acid transferase (GABA-T) or in nerve terminals by the hydrolysis of glutamine by the enzyme glutaminase. GABA is synthesized by the conversion of glutamate by the enzyme glutamic acid decarboxylase (GAD). B) Acetylcholine is synthesized in the cytoplasm of a nerve terminal from acetyl-Co-A and choline by the enzyme choline acetyltransferase. C) Serotonin is synthesized from the amino acid tryptophan in a two-step process: the enzymatic hydroxylation of tryptophan to 5-hydroxytryptophan and the enzymatic decarboxylation of this intermediate to form 5-hydroxytryptamine (also called serotonin). D) Catecholamines are synthesized from the amino acid tyrosine by a multi-step process. Tyrosine is oxidized to dihydroxyphenylalanine (DOPA) by the enzyme tyrosine hydroxylase in the cytoplasm of the neuron; DOPA is then decarboxylated to dopamine. In dopaminergic neurons, the process stops there. In noradrenergic neurons, the dopamine is transported into synaptic vesicles where it is converted to norepinephrine by dopamine-β hydroxylase. In neurons that also contain the enzyme phenylethanolamine-N-methyltransferase, norepinephrine is converted to epinephrine.
Fig2. Four diffusely connected systems of central neuromodulators. A) Noradrenergic neurons in the locus coeruleus innervate the spinal cord, cerebellum, several nuclei of the hypothalamus, thalamus, basal telencephalon, and neocortex. B) Serotonergic neurons in the raphe nuclei project to the hypothalamus, limbic system, neocortex, cerebellum, and spinal cord. C) Dopaminergic neurons in the substantia nigra project to the striatum and those in the ventral tegmental area of the midbrain project to the prefrontal cortex of the limbic system. D) Cholinergic neurons in the basal forebrain complex project to the hippocampus and the neocortex and those in the pontomesencephalotegmental cholinergic complex project to the dorsal thalamus and the forebrain. (Reproduced with permission from Boron WF, Boulpaep EL: Medical Physiology. St. Louis, MO: Elsevier; 2005.)
RECEPTORS
The action of a chemical mediator on its target structure is more dependent on the type of receptor on which it acts than on the properties of the mediator per se. Cloning and other molecular biology techniques have permitted spectacular advances in knowledge about the structure and function of receptors for neurotransmitters and other chemical messengers. The individual receptors, along with their ligands (the molecules that bind to them), are discussed in the following parts of this chapter. However, five themes have emerged that should be mentioned in this introductory discussion.
First, in every instance studied in detail to date, each chemical mediator has the potential to act on many subtypes of receptors. Thus, for example, norepinephrine acts on α1-, α2-, β1-, β2-, and β3-adrenergic receptors. Obviously, this multi plies the possible effects of a given ligand and makes its effects in a given cell more selective.
Second, there are receptors on the presynaptic as well as the postsynaptic elements for many secreted transmitters. One type of presynaptic receptor called an autoreceptor often inhibits further secretion of the transmitter, providing feedback control. For example, norepinephrine acts on α2-presynaptic receptors to inhibit additional norepinephrine secretion. A second type of presynaptic receptor is called a heteroreceptor whose ligand is a chemical other than the transmitter released by the nerve ending on which the receptor is located. For example, norepinephrine acts on a heteroreceptor on a cholinergic nerve terminal to inhibit the release of acetylcholine. In some cases, presynaptic receptors facilitate the release of neurotransmitters.
Third, although there are many neurotransmitters and many subtypes of receptors for each ligand, the receptors tend to group in two large families in terms of structure and func tion: ligand-gated channels (also known as ionotropic receptors) and metabotropic receptors. In the case of ionotropic receptors, a membrane channel is opened when a ligand binds to the receptor; and activation of the channel usually elicits a brief (few to tens of milliseconds) increase in ionic conductance. Thus, these receptors are important for fast synaptic transmission. Metabotropic receptors are 7-transmembrane G-protein–coupled receptors (GPCR), and binding of a neurotransmitter to these receptors initiates the production of a second messenger that modulates the voltage-gated channels on neuronal membranes. The receptors for some neurotransmitters and neuromodulators are listed in Table 2, along with their principal second messengers and, where established, their net effect on ion channels. It should be noted that this table is an over-simplification. For example, activation of α2-adrenergic receptors decreases intracellular cyclic adenosine monophosphate (cAMP) concentrations, but there is evidence that the G-protein activated by α2-adrenergic presynaptic receptors also acts directly on Ca2+ channels to inhibit norepinephrine release.
Table2. Pharmacology of a selection of receptors for some small-molecule neurotransmitters.
Fourth, receptors are concentrated in clusters on the postsynaptic membrane close to the endings of neurons that secrete the neurotransmitters specific for them. This is generally due to the presence of specific binding proteins for them.
Fifth, in response to prolonged exposure to their ligands, most receptors become unresponsive; that is, they undergo desensitization. This can be of two types: homologous desensitization, with loss of responsiveness only to the particular ligand and maintained responsiveness of the cell to other ligands; and heterologous desensitization, in which the cell becomes unresponsive to other ligands as well.
REUPTAKE
Neurotransmitters are rapidly transported from the synaptic cleft back into the cytoplasm of the neurons that secreted them via a process called reuptake, which involves a high-affinity, Na+-dependent membrane transporter. Figure 3 illustrates the principle of reuptake of norepinephrine released from a sympathetic postganglionic nerve. After release of norepinephrine into the synaptic cleft, it is rapidly routed back into the sympathetic nerve terminal by a norepinephrine transporter (NET). A portion of the norepinephrine that re-enters the neuron is sequestered into the synaptic vesicles through the vesicular monoamine transporter (VMAT). There are analogous membrane and vesicular transporters for other small-molecule neurotrans mitters released at other synapses in the CNS and peripheral nervous system.
Fig3. Fate of monoamines secreted at synaptic junctions. In each monoamine-secreting neuron, the monoamine is synthesized in the cytoplasm and the secretory granules and its concentration in secretory granules is maintained by the two vesicular monoamine transporters (VMAT). The monoamine is secreted by exocytosis of the granules, and it acts on G-protein coupled receptors. In this example, the monoamine is norepinephrine acting on adrenoceptors. Many of these receptors are postsynaptic, but some are presynaptic and some are located on glia. In addition, there is extensive reuptake of the monoamine into the cytoplasm of the presynaptic terminal via a monoamine transporter, in this case the norepinephrine transporter (NET). (Modified with permission from Katzung BG, Masters SB, Trevor AJ: Basic and Clinical Pharmacology, 11th ed. New York, NY: McGraw-Hill; 2009.)
Reuptake is a major factor in terminating the action of transmitters, and when it is inhibited, the effects of transmitter release are increased and prolonged. This has clinical consequences. For example, several effective antidepressant drugs are inhibitors of the reuptake of amine transmitters, and cocaine may inhibit dopamine reuptake. Glutamate uptake into neurons and glia is important because glutamate is an excitotoxin that can kill cells by overstimulating them (see Clinical Box 1). There is evidence that during ischemia and anoxia, loss of neurons is increased because glutamate reuptake is inhibited.
Clinical Box 1
