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

HSP70
S
GR
S
GR
HSP90
S
GR
GRE GRE
CBG
S
IP
Transcription
protein
CBG
GR
HSP90
nucleus
gene
mRNA
cytoplasm
Altered cellular function
apparent after several hours. This fact is of clinical significance
because a delay generally is seen before beneficial
effects of corticosteroid therapy become manifest.
Although corticosteroids predominantly act by increasing
gene transcription, there are well-documented examples
in which glucocorticoids decrease gene transcription,
as discussed later. In addition, corticosteroids may exert
some of their immediate effects by nongenomic mechanisms
(Stahn and Buttgereit, 2008).
IP
HSP70
Figure 42–5. Intracellular mechanism of action of the glucocorticoid
receptor. The figure shows the molecular pathway by
which cortisol (labeled S) enters cells and interacts with the glucocorticoid
receptor (GR) to change GR conformation (indicated
by the change in shape of the GR), induce GR nuclear translocation,
and activate transcription of target genes. The example
shown is one in which glucocorticoids activate expression of
target genes; the expression of certain genes, including proopiomelanocortin
(POMC) expression by corticotropes, is inhibited
by glucocorticoid treatment. CBG, corticosteroid-binding
globulin; GR, glucocorticoid receptor; S, steroid hormone;
HSP90, the 90-kd heat-shock protein; HSP70, the 70-kd heatshock
protein; IP, the 56-kd immunophilin; GRE, glucocorticoidresponse
elements in the DNA that are bound by GR, thus
providing specificity to induction of gene transcription by glucocorticoids.
Within the gene are introns (gray) and exons (red);
transcription and mRNA processing leads to splicing and
removal of introns and assembly of exons into mRNA.
S
Glucocorticoid Receptors. The receptors for corticosteroids are members
of the nuclear receptor family of transcription factors that transduce
the effects of a diverse array of small hydrophobic ligands,
including the steroid hormones, thyroid hormone, vitamin D, and
retinoids. These receptors share two highly conserved domains: a
region of ~70 amino acids forming two zinc-binding domains, called
zinc fingers, that are essential for the interaction of the receptor with
specific DNA sequences, and a region at the carboxyl terminus that
interacts with ligand (the ligand-binding domain). The GR resides
predominantly in the cytoplasm in an inactive form until it binds glucocorticoids
(Figure 42–5). Steroid binding results in receptor activation
and translocation to the nucleus. The inactive GR is
complexed with other proteins, including heat-shock protein (HSP)
90, a member of the heat-shock family of stress-induced proteins;
HSP70; and a 56,000-Da immunophilin, one of the group of intracellular
proteins that bind the immunosuppressive agents
cyclosporine and tacrolimus (see Chapter 35). HSP90, through interactions
with the steroid-binding domain, may facilitate folding of
the GR into an appropriate conformation that permits ligand binding.
The gene encoding the GR is located on human chromosome
5 and gives rise to several receptor isoforms as the result of alternative
RNA splicing. Of these, GRα is the prototypical glucocorticoidresponsive
isoform already discussed and is the best studied. A
second major GR isoform, GRβ, is a truncated dominant negative
variant that lacks 35 amino acids at the C-terminus and is unable to
bind glucocorticoids or activate gene expression. GRβ expression is
enhanced by tumor necrosis factor α and other pro-inflammatory
cytokines and its relative abundance is thought to contribute to glucocorticoid
resistance in some patients. Other splice variants have
been identified that retain their ligand-binding activity but have
amino acid insertions or deletions of the DNA-binding domain that
reduce their transcriptional activity (Gross and Cidlowski, 2008).
Finally, polymorphisms have been identified in the human GR that
are associated with differences in GR function and have been linked
to glucocorticoid insensitivity (Derijk et al., 2008).
Although complete loss of GR function apparently is lethal,
mutations leading to partial loss of GR function occur in rare patients
with generalized glucocorticoid resistance (Charmandari et al.,
2008). These patients harbor mutations in the GR, most of which
impair glucocorticoid binding and decrease transcriptional activation.
As a consequence of these mutations, cortisol levels that normally
mediate feedback inhibition fail to suppress the HPA axis
completely. In this setting of partial loss of GR function, the HPA
axis resets to a higher level to provide compensatory increases in
ACTH and cortisol secretion. Because the GR defect is partial, adequate
compensation for the end-organ insensitivity can result from
the elevated cortisol level, but the excess ACTH secretion also stimulates
the production of mineralocorticoids and adrenal androgens.
Because the mineralocorticoid receptor (MR) and the androgen
receptor are intact, these subjects present with manifestations of mineralocorticoid
excess (hypertension and hypokalemic alkalosis)
and/or of increased androgen levels (acne, hirsutism, male pattern
baldness, menstrual irregularities, anovulation, and infertility). In
children, the excess adrenal androgens can cause precocious sexual
development.
Regulation of Gene Expression by Glucocorticoids. After ligand binding,
the GR dissociates from its associated proteins and translocates
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CHAPTER 42
ACTH, ADRENAL STEROIDS, AND PHARMACOLOGY OF THE ADRENAL CORTEX