130
SECTION II
Physiology of Nerve & Muscle Cells
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
α
1
and
α
2
recep-
tors, and three of each subtype have been cloned. In addition,
there are
β
1
,
β
2
, and
β
3
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
α
2
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
α
2
-adrenergic recep-
tors decreases intracellular cAMP concentrations, but there is
evidence that the G protein activated by
α
2
-adrenergic presyn-
aptic receptors also acts directly on Ca
2+
channels to inhibit
norepinephrine release by decreasing Ca
2+
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.
GABA
A
receptors are associated with the protein
gephyrin,
which also binds glycine receptors, and GABA
C
receptors are
bound to the cytoskeleton in the retina by the protein
MAP-1B.
At least in the case of GABA
A
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