710
chapter 30
Endocrine Metabolism I: Introduction
is a means by which a cell protects itself against exces-
sive hormonal stimulation. Insulin, the catecholamines,
GnRH, endogenous opiates, and epidermal growth factor
downregulate their receptors. “Upregulation” (increase in
receptor number) also occurs. Prolactin, for example, up-
regulates its receptors in the mammary gland.
Heterologous regulation is more widespread and is a
mechanism by which certain hormones influence the ac-
tions of other hormones. Some hormones diminish the
production of receptors for another hormone thereby exert-
ing an antagonistic effect. Growth hormone, for example,
causes reduction in the number of insulin receptors. More
prevalent, however, is augmentation of receptor number by
a heterologous hormone. Estrogen, for example, increases
the number of receptors for the progesterone, oxytocin,
and LH, while thyroid hormone increases the number of
/
1
-adrenergic receptors in some tissues.
Hormone receptors can be classified into three types
on the basis of their locations in the cell and the types of
hormone they bind:
1. Nuclear receptors, which bind triiodothyronine (T3)
after it enters the cell;
2. Cytosolic receptors, which bind steroid hormones as
they diffuse into the cell; and
3. Cell surface receptors, which detect water-soluble
hormones that do not enter the cell (peptides,
proteins, glycoproteins, catecholamines). The
mechanism of action of each of these receptor types is
different because each is associated with different
postreceptor events in the cell.
30.5 Types of Hormone Receptors
Nuclear Receptors
Receptors for thyroid hormone (TR), 1,25-dihydroxy-
vitamin D (VDR), and retinoic acid (RAR) are called
nuclear receptors
because they are located in the nucleus
already bound to DNA (nuclear chromatin) even in the
absence of their respective hormone or ligand. These nu-
clear receptors closely resemble the steroid hormone re-
ceptors and belong to the same “superfamily” of DNA-
binding proteins. The similarities among the members of
this superfamily are striking, particularly in their DNA
recognition domains and in the corresponding receptor
recognition segment of DNA. The receptor molecule con-
sists of three domains: a carboxy terminal that binds the
ligand (hormone/vitamin), a central DNA binding do-
main (DBD), and an amino terminal that may function
as a gene enhancer. The ligand binding domain has high
specificity for the ligand, and is the trigger that initiates
receptor-mediated regulation of gene expression by the
ligand. The receptor is bound to DNA by way of two
“zinc fingers” (Chapter 26) in the DBD, which associates
with a specific nucleotide sequence in DNA called the “re-
sponse element” for the ligand. The response element is
usually located “upstream” (at the 5' end) of a promoter
for the gene that is regulated by the ligand, such that bind-
ing of the ligand to the receptor activates the response
element (via the DBD), which then activates (“transacti-
vates”) transcription of the gene. Transactivation of gene
transcription involves the binding of RNA polymerase II
to the promoter region of the gene and construction of an
RNA transcript (hnRNA) from the DNA gene sequence
(Figure 30-3). The hnRNA is then spliced to yield mature
mRNA (messenger RNA), which translocates to the cyto-
plasmic compartment and becomes associated with ribo-
somes. Ribosomal translation of the mRNA results in the
synthesis of a nascent polypeptide, the primary sequence
of which is encoded in the gene that was activated by the
ligand.
Thyroid Hormone Receptors
Thyroid hormone receptors
(TRs) are nonhistone proteins
that function as transducers of the effects of thyroid hor-
mone on gene expression. There are four isoforms of TR
(TRa 1, TRa2, TR/31, TR/J2) that are products of two dif-
ferent genes,
c-erbAa
and
c-erbAfi.
There is some tissue
specificity in the distribution of these isoforms. Three of
these isoforms (TRa 1, TRa2, TR/31) are found in almost
all cells (although in different relative amounts); however,
the TR/32 isoform is found only in the brain. The TRa2 is
unique because it does not bind thyroid hormone but it does
bind to DNA. Its function is unclear. The other three TR
isoforms are single proteins with three regions (domains):
a carboxy terminal region that binds T3, a central region
that binds a specific region of DNA, and an amino terminal
region that may function as a gene enhancer. The TR is syn-
thesized on ribosomes and is actively transported through
the nuclear membrane pores into the nucleus, where the
DBD of the TR binds to a specific segment of DNA called
the “thyroid hormone response element” (TRE). The TR
binds to a TRE half-site as a monomer, a homodimer
(ala,
«//3,
pip,
etc.) or a heterodimer, in which a TR isoform
dimerizes with another protein, e.g., the retinoid X recep-
tor (RXR). In the absence of thyroid hormone, the TR
association with the TRE does not result in any changes in
gene expression. Thus, TRs exist in the nucleus, are bound
to DNA, and await the arrival of thyroid hormone.
Thyroid hormones T
4
and T
3
arrive at their target cells
by transport in plasma, for the most part bound to plasma
proteins (Chapter 33). The very small fraction of T
4
and
