section 30.5

Types of Hormone Receptors

711

Ligand

FIGURE 30-3

Thyroid hormone, 1,25-dihydroxy vitamin D, and retinoic acid receptor regulation of transcription. The hormone

receptor (HR) is dimerized at site (3) and is bound to DNA at hormone response element site (2). Without the ligand,

transcription is inactive due to the interaction of HR with corepressor at site 4. When the ligand (hormone) binds to HR,

the bound corepressor dissociates leading to an interaction between the coactivator and HR. These regulatory changes

result in increased transcription.

T

3

that is unbound at any given instant is accessible for

cellular “uptake,” i.e., the diffusional passage of the hy-

drophobic hormone through the lipid matrix of the cell

membrane and into the cell. Once in the cell, the hormone

associates loosely with cytoplasmic proteins that prevent

its escape back into plasma. Microsomal 5'-deiodinase,

which is present in thyroid target cells, catalyzes the re-

moval of the 5'-iodine from T4, converting it to T3. This

creates a concentration gradient that favors the movement

of hormone into the nuclear compartment, in which TR

(monomer or dimers) exists in association with the TRE

sequence of DNA. Monomeric TR appears to bind to a

TRE half-site, while dimeric (homodimer or heterodimer)

TR binds to two half-sites. When activated by T

3

bind-

ing to TR, the TRE promotes transcription of the gene

into hnRNA. After removal of the introns from hnRNA,

the resultant mRNA is translated into a protein at the

ribosomes. The protein, which may be regulatory or struc-

tural, is the final molecular expression of thyroid hormone

action.

The outcome of T

3

binding to TR is not a stimulation of

transcription in all cases. In the pituitary thyrotrophs, T

3

inhibits transcription of both the TSH-a and TSH-/3 genes

by binding to TR-TRE complexes. The TR mediating this

inhibitory effect appears to be a monomer that binds to

a TRE half-site, in contrast to the usual dimeric TR that

binds to two TRE half-sites and mediates the stimulatory

effects of T

3

on transcription in other cell types.

In some instances, the actual cell response to thyroid

hormone is a manifestation of the activity of the induced

protein; therefore, the induced protein would first need to

be activated (e.g., by phosphorylation) before the thyroid

hormone effect on the cell can be seen.

Steroid Hormone Receptors

Steroid hormone receptors

belong to a large family of

DNA-binding proteins that include receptors for thyroid

hormone, retinoic acid, and l,25(OH)2 vitamin D. There

are specific receptors for glucocorticoids (GRs), mineralo-

corticoids (MRs), estrogens (ERs), androgens (ARs), and

progestogens (PRs), all of which are coded for by different

genes. Unlike the TR, there appears to be only one func-

tional receptor protein for a given steroid that is encoded on

a single gene. Like the TR, the steroid receptor is a single

protein with three regions (domains): a carboxy terminal

region that binds the steroid specifically, a central DBD,

and an amino terminal region that may function as a gene

enhancer. The DBD of the steroid receptor projects two

zinc fingers that allows both recognition of and binding to

the hormone response element (HRE) of DNA.

A generic depiction of the mechanism for steroid hor-

mone activity at a target cell is shown in Figure 30-4. The

first step consists of dissociation of the hormone from the

plasma transport protein and entry into the cell by diffu-

sion across the plasma membrane. In the second step the

hormone binds with the receptors in the cytoplasm and

nucleus. Receptors for glucocorticoid and aldosterone are

found in the cytoplasm and receptors for estrogen and pro-

gesterone are found in the nucleus. Recall that receptors for