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include monoamines (eg, acetylcholine, serotonin, hista- mine), catecholamines (dopamine, norepinephrine, and epi- nephrine), and amino acids (eg, glutamate, GABA, glycine).
Large-molecule transmitters include a large number of pep- tides called neuropeptides including substance P, enkephalin, vasopressin, and a host of others. In general, neuropeptides are colocalized with one of the small-molecule neurotransmitters (Table 7–1).
There are also other substances thought to be released into the synaptic cleft to act as either a transmitter or modulator of synaptic transmission. These include purine derivatives like adenosine and adenosine triphosphate (ATP) and a gaseous molecule, nitric oxide (NO).
Figure 7–1 shows the biosynthesis of some common small- molecule transmitters released by neurons in the central or peripheral nervous system. Figure 7–2 shows the location of major groups of neurons that contain norepinephrine, epi- nephrine, dopamine, and acetylcholine. These are some of the major neuromodulatory systems.
RECEPTORS
Cloning and other molecular biology techniques have permit- ted spectacular advances in knowledge about the structure and function of receptors for neurotransmitters and other chemi- cal messengers. The individual receptors, along with their
ligands, 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, it has become clear that each ligand has many subtypes of receptors.
Thus, for example, norepinephrine acts on α1 and α2 recep- tors, and three of each subtype have been cloned. In addition, there are β1, β2, and β3 receptors. Obviously, this multiplies 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. These presynaptic receptors, or autoreceptors, often inhibit fur- ther secretion of the ligand, providing feedback control. For example, norepinephrine acts on α2 presynaptic receptors to inhibit norepinephrine secretion. However, autoreceptors can also facilitate the release of neurotransmitters.
Third, although there are many ligands and many subtypes of receptors for each ligand, the receptors tend to group in large families as far as structure and function are concerned.
Many receptors act via trimeric G proteins and protein kinases to produce their effects. Others are ion channels. The receptors for a group of selected, established neurotransmitters and neu- romodulators are listed in Table 7–2, along with their princi- pal 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 recep- tors decreases intracellular cAMP concentrations, but there is evidence that the G protein activated by α2-adrenergic presyn- aptic receptors also acts directly on Ca2+ channels to inhibit norepinephrine release by decreasing Ca2+ increases.
Fourth, receptors are concentrated in clusters in postsynaptic structures close to the endings of neurons that secrete the neu- rotransmitters specific for them. This is generally due to the presence of specific binding proteins for them. In the case of nic- otinic acetylcholine receptors at the neuromuscular junction, the protein is rapsyn, and in the case of excitatory glutamatergic receptors, a family of PB2-binding proteins is involved.
GABAA receptors are associated with the protein gephyrin, which also binds glycine receptors, and GABAC receptors are bound to the cytoskeleton in the retina by the protein MAP-1B.
At least in the case of GABAA receptors, the binding protein gephyrin is located in clumps in the postsynaptic membrane.
With activity, the free receptors move rapidly to the gephyrin and bind to it, creating membrane clusters. Gephyrin binding slows and restricts their further movement. Presumably, during neural inactivity, the receptors are unbound and move again.
Fifth, prolonged exposure to their ligands causes most receptors to become unresponsive, that is, to undergo desensi- tization. This can be of two types: homologous desensitiza- tion, 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. Desensitization in β- adrenergic receptors has been studied in considerable detail.
One form involves phosphorylation of the carboxyl terminal
TABLE 7–1
Examples of colocalization of small-molecule transmitters with neuropeptides.Small-Molecule
Transmitter Neuropeptide Monoamines
Acetylcholine Enkephalin, calcitonin-gene-related peptide, galanin, gonadotropin-releasing hormone, neurotensin, somatostatin, substance P, vaso- active intestinal polypeptide
Serotonin Cholecystokinin, enkephalin, neuropeptide Y, substance P, vasoactive intestinal polypeptide Catecholamines
Dopamine Cholecystokinin, enkephalin, neurotensin Norepinephrine Enkephalin, neuropeptide Y, neurotensin, so-
matostatin, vasopressin
Epinephrine Enkephalin, neuropeptide Y, neurotensin, substance P
Amino Acids
Glutamate Substance P
Glycine Neurotensin
GABA Cholecystokinin, enkephalin, somatostatin, substance P, thyrotropin-releasing hormone
CHAPTER 7 Neurotransmitters & Neuromodulators 131
FIGURE 7–1 Biosynthesis of some common small molecule transmitters. (Reproduced with permission from Boron WF, Boulpaep EL: Medical Physiology. Elsevier, 2005.)
132 SECTION II Physiology of Nerve & Muscle Cells
region of the receptor by a specific β-adrenergic receptor kinase (β-ARK) or binding β-arrestins. Four β-arrestins have been described in mammals. Two are expressed in rods and cones of the retina and inhibit visual responses. The other two, β-arrestin 1 and β-arrestin 2, are more ubiquitous. They desensitize β-adrenegic receptors, but they also inhibit other heterotrimeric G protein-coupled receptors. In addition, they foster endocytosis of ligands, adding to desensitization.