DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

1110
A
GH
B
GH
GH
Pegvisomant
G
H
R
G
H
R
G
H
R
G
H
R
G
H
R
G
H
R
RS-1
SHC
J
A
K
2
STAT5
J
A
K
2
No GH
signaling
SECTION V
P3K
MAPK
Gene expression
(e.g., GF-1)
HORMONES AND HORMONE ANTAGONISTS
Glucose
transporter
Nucleus
Figure 38–5. Mechanisms of growth hormone and prolactin action and of GH receptor antagonism. Left (A): The binding of GH to a
homodimer of the growth hormone receptor (GHR) induces autophosphorylation of JAK2. JAK2 then phosphorylates cytoplasmic proteins
that activate downstream signaling pathways, including STAT5 and mediators upstream of MAPK, which ultimately modulate
gene expression. The structurally related prolactin receptor also is a ligand activated homodimer that recruits the JAK-STAT signaling
pathway (see text for further details). The GHR also activates IRS-1, which may mediate the increased expression of glucose
transporters on the plasma membrane. The diagram does not reflect the localization of the intracellular molecules, which presumably
exist in multicomponent signaling complexes. JAK2, janus kinase 2; IRS-1, insulin receptor substrate-1; PI3K, phosphatidyl inositol-3
kinase; STAT, signal transducer and activator of transcription; MAPK, mitogen-activated protein kinase; SHC, Src homology
containing. Right (B): Pegvisomant, a recombinant pegylated variant of human GH, contains amino acid substitutions that increase
the affinity for one site of the GHR but do not activate its downstream signaling cascade. It thus interferes with GH signaling in target
tissues.
lactogen, which also bind to the prolactin receptor and thus are lactogenic,
prolactin binds specifically to the prolactin receptor and has
no somatotropic (GH-like) activity.
Physiological Effects of the Somatotropic Hormones.
The most striking physiological effect of GH—and the
basis for its name—is the stimulation of the longitudinal
growth of bones (Giustina et al., 2008). GH also
increases bone mineral density after the epiphyses have
closed and longitudinal growth ceases. These effects of
GH involve the differentiation of prechondrocytes to
chondrocytes and stimulation of osteoclast and osteoblast
proliferation. Other effects of GH include the stimulation
of myoblast differentiation (in experimental animals)
and increased muscle mass (in human subjects with GH
deficiency), increased glomerular filtration rate, and
stimulation of preadipocyte differentiation into
adipocytes. GH has potent anti-insulin actions in both the
liver and peripheral sites (e.g., adipocytes and muscle) that
decrease glucose utilization and increase lipolysis.
Finally, GH has been implicated in the development and
function of the immune system.
Growth hormone acts directly on adipocytes to
increase lipolysis and on hepatocytes to stimulate gluconeogenesis,
but its anabolic and growth-promoting
effects are mediated indirectly through the induction of
IGF-1. Although most circulating IGF-1 is made in the
liver, IGF-1 produced locally in many tissues is critical
for growth, as revealed by normal growth in mice that
have a hepatocyte-specific inactivation of IGF-1.
Circulating IGF-1 is associated with a family of binding
proteins, designated the IGF-binding proteins
(IGFBPs), that serve as transport proteins and also may
mediate certain aspects of IGF-1 signaling. Most IGF-1
in circulation is bound to IGFBP-3 and another protein
called the acid-labile subunit.
The essential role of IGF-1 in growth is evidenced
by patients with loss-of-function mutations in both alleles
of the IGF1 gene, whose severe intrauterine and