section 30.2
Peptide, Protein, and Glycoprotein Hormones
701
them are modified postsynaptic neurons (e.g., adrenal
medulla), blood-derived cells (e.g., basophils, mast cells),
or APUD
1
cells (e.g., enterochromaffin cells). Regardless
of where they are released, hormonal amines exert their
effects through specific receptor sites located in various
parts of the body. These systemic receptors (Table 30-1)
and their subtypes probably have identical counterparts in
the central and peripheral nervous systems. All of these
amines except T
3
exert rapid systemic effects that usually
involve smooth-muscle activity. Because the amines are
hydrophilic, their receptors are located on the outer sur-
face of target cells, and most if not all of their effects are
mediated by intracellular mediators.
30.2 Peptide, Protein, and
Glycoprotein Hormones
Cells that produce peptide, protein, or glycoprotein hor-
mones are derived embryologically from the entoderm
or ectoblast (progenitor of ectoderm and neuroectoderm).
More than 40 hormones have been identified, containing
from three to over 200 amino acid residues. Table 30-2 lists
the important hormones and hormonal candidates, number
of amino acid residues, and sites of synthesis.
All hormonal peptides and many hormonal proteins are
synthesized as part of a larger molecule (
preprohormone
)
that contains a leader sequence (signal peptide) at its
amino terminal end. The leader sequence is removed
as the nascent precursor enters the lumen of the endoplas-
mic reticulum, and the resultant prohormone undergoes
posttranslational processing after being packaged into
secretory granules by the Golgi complex. Posttranslational
processing involves proteolytic cleavage at specific sites,
usually paired basic amino acid residues (Lys-Arg, Arg-
Lys, Arg-Arg, Lys-Lys), by endopeptidases within the se-
cretory granule. In the synthesis of insulin, for example,
removal of the 23-amino-acid leader sequence of pre-
proinsulin results in proinsulin, which has two pairs of
basic residues (Lys-Arg and Arg-Arg) that are cleaved to
yield insulin and the C-peptide (Chapter 22). Likewise,
the endogenous opiates arise from site-specific cleavages
of their respective prohormones (Chapter 31). When the
cell is stimulated to secrete, all major fragments of the
prophormone, active and inactive, are released by calcium-
dependent exocytosis. *
*APUD (amine precursor uptake and decarboxylation) cells are derived
from the neuroblast (stem cells that give rise to nerve cells and neural crest
cells) or the entoderm. They have the ability to synthesize and release peptide
hormones and, as their name implies, take up amine precursors (e.g., dopa)
and decarboxylate them, producing hormonal amines (e.g., dopamine).
Although several peptide hormones have multiple
anatomical sites of synthesis, there is usually only one im-
portant source of the circulating hormone. The presence
of the same hormone in ancillary sites (Table 30-2) may
indicate that it functions as a local hormone at those sites.
For example, somatostatin produced by the hypothalamus
is transported by blood to the anterior pituitary, where
it inhibits the release of growth hormone (GH); somato-
statin produced by the hypothalamus also functions as an
inhibitory neurotransmitter when released into synapses
in the central nervous system; somatostatin produced by
pancreatic islet cells acts locally to inhibit the release of
insulin and glucagon; and somatostatin produced by the
gastrointestinal mucosa acts locally to inhibit the secre-
tion of gastrin, secretin, and gastric inhibitory polypeptide
(GIP). Other “brain-gut” peptides(Chapter 31) also exem-
plify this point, although they are not released into the
general circulation in significant amounts.
Peptide hormones, because of their high information
content,may have evolved from a limited number of ances-
tral molecules that functioned as intercellular messengers
or as extracellular enzymes. Thus, some exhibit homol-
ogy in their amino acid sequences, suggesting the same
(or similar) evolutionary roots. Several families of pep-
tides have been described, including the opiomelanocortin
family (endorphin, adrenocorticotropic hormone, melano-
cyte-stimulating
hormone),
the
somatomammotropin
family (growth hormone, prolactin, human placental lac-
togen), the glycoprotein hormones (thyroid-stimulating
hormone, luteinizing hormone, follicle-stimulating hor-
mone, human chorionic gonadotropin), the insulin family
(insulin, insulin-like growth factors, somatomedins, re-
laxing and the secretin family (secretin, glucagon, gli-
centin, gastric inhibitory peptide, vasoactive intestinal
peptide). Members in a family are related in structure
and function. Thus, members of the secretin family stimu-
late secretory activity in target cells, while those of the
insulin family promote cell growth. This preservation
of structure and function can be traced to more prim-
itive forms of life. For example, “a-mating factor,” a
primitive relative of mammalian gonadotropin-releasing
hormone (GnRH) with which it shares 80% sequence
homology, functions as a reproductive pheromone in
yeast. Moreover, mammalian corticotropin-releasing hor-
mone (CRH) is related to urotensin I of teleosts and to
sauvagine of amphibians in structure and in the ability
to cause hypotension, vasodilatation, and ACTH release
when administered to mammals. Certain strains of bac-
teria synthesize substances indistinguishable from mam-
malian hCG and TSH and also synthesize serine pro-
teases that are structurally homologous to the subunits
of the glycoprotein hormones. Glycoprotein hormones
