138 SECTION IIPhysiology of Nerve & Muscle Cells
sexual behavior, blood pressure, drinking, pain thresholds,
and regulation of the secretion of several anterior pituitary
hormones.
CATECHOLAMINES
Norepinephrine & Epinephrine
The chemical transmitter present at most sympathetic post-
ganglionic endings is norepinephrine. It is stored in the syn-
aptic knobs of the neurons that secrete it in characteristic
small vesicles that have a dense core (granulated vesicles; see
above). Norepinephrine and its methyl derivative, epineph-
rine, are secreted by the adrenal medulla, but epinephrine is
not a mediator at postganglionic sympathetic endings. As
discussed in Chapter 6, each sympathetic postganglionic
neuron has multiple varicosities along its course, and each of
these varicosities appears to be a site at which norepineph-
rine is secreted.
There are also norepinephrine-secreting and epinephrine-
secreting neurons in the brain. Norepinephrine-secreting neu-
rons are properly called noradrenergic neurons, although the
term adrenergic neurons is also applied. However, it seems
appropriate to reserve the latter term for epinephrine-secreting
neurons. The cell bodies of the norepinephrine-containing
neurons are located in the locus ceruleus and other medullary
and pontine nuclei (Figure 7–2). From the locus ceruleus, the
axons of the noradrenergic neurons form the locus ceruleus
system. They descend into the spinal cord, enter the cerebel-
lum, and ascend to innervate the paraventricular, supraoptic,
and periventricular nuclei of the hypothalamus, the thalamus,
the basal telencephalon, and the entire neocortex.
Biosynthesis & Release of Catecholamines
The principal catecholamines found in the body—norepi-
nephrine, epinephrine, and dopamine—are formed by hy-
droxylation and decarboxylation of the amino acid tyrosine
(Figure 7–1). Some of the tyrosine is formed from phenylala-
nine, but most is of dietary origin. Phenylalanine hydroxylase
is found primarily in the liver (see Clinical Box 7–3). Tyrosine
is transported into catecholamine-secreting neurons and ad-
renal medullary cells by a concentrating mechanism. It is con-
verted to dopa and then to dopamine in the cytoplasm of the
cells by tyrosine hydroxylase and dopa decarboxylase. The
decarboxylase, which is also called aromatic L-amino acid de-
carboxylase, is very similar but probably not identical to 5-hy-
droxytryptophan decarboxylase. The dopamine then enters
the granulated vesicles, within which it is converted to norepi-
nephrine by dopamine β-hydroxylase (DBH). L-Dopa is the
isomer involved, but the norepinephrine that is formed is in
the D configuration. The rate-limiting step in synthesis is the
conversion of tyrosine to dopa. Tyrosine hydroxylase, which
catalyzes this step, is subject to feedback inhibition by dopa-
mine and norepinephrine, thus providing internal control of
the synthetic process. The cofactor for tyrosine hydroxylase is
tetrahydrobiopterin, which is converted to dihydrobiopterin
when tyrosine is converted to dopa.
Some neurons and adrenal medullary cells also contain the
cytoplasmic enzyme phenylethanolamine-N-methyltrans-
ferase (PNMT), which catalyzes the conversion of norepineph-
rine to epinephrine. In these cells, norepinephrine apparently
leaves the vesicles, is converted to epinephrine, and then enters
other storage vesicles.
In granulated vesicles, norepinephrine and epinephrine are
bound to ATP and associated with a protein called chromo-
granin A. In some but not all noradrenergic neurons, the
large granulated vesicles also contain neuropeptide Y. Chro-
mogranin A is a 49-kDa acid protein that is also found in
many other neuroendocrine cells and neurons. Six related
chromogranins have been identified. They have been
claimed to have multiple intracellular and extracellular func-
tions. Their level in the plasma is elevated in patients with a
variety of tumors and in essential hypertension, in which they
probably reflect increased sympathetic activity. However,
their specific functions remain unsettled.
The catecholamines are transported into the granulated
vesicles by two vesicular transporters, and these transporters
are inhibited by the drug reserpine.
Catecholamines are released from autonomic neurons and
adrenal medullary cells by exocytosis. Because they are present
in the granulated vesicles, ATP, chromogranin A, and theCLINICAL BOX 7–3
Phenylketonuria
Phenylketonuria is a disorder characterized by severe men-
tal deficiency and the accumulation in the blood, tissues, and
urine of large amounts of phenylalanine and its keto acid
derivatives. It is usually due to decreased function resulting
from mutation of the gene for phenylalanine hydroxylase.
This gene is located on the long arm of chromosome 12. Cat-
echolamines are still formed from tyrosine, and the cognitive
impairment is largely due to accumulation of phenylalanine
and its derivatives in the blood. Therefore, it can be treated
with considerable success by markedly reducing the amount
of phenylalanine in the diet. The condition can also be
caused by tetrahydrobiopterin (BH4) deficiency. Because
BH4 is a cofactor for tyrosine hydroxylase and tryptophan
hydroxylase, as well as phenylalanine hydroxylase, cases due
to tetrahydrobiopterin deficiency have catecholamine and
serotonin deficiencies in addition to hyperphenylalaninemia.
These cause hypotonia, inactivity, and developmental prob-
lems. They are treated with tetrahydrobiopterin, levodopa,
and 5-hydroxytryptophan in addition to a low-phenylalanine
diet. BH4 is also essential for the synthesis of nitric oxide (NO)
by nitric oxide synthase. Severe BH4 deficiency can lead to
impairment of NO formation, and the CNS may be subjected
to increased oxidative stress.