Human Physiology, 14th edition (2016)

324 Chapter 11

Modern molecular biology has ushered in a new era in

endocrine research, where nuclear receptors can be identified

and their genes cloned before their hormone ligands are known.

In fact, scientists have currently identified the hormone ligand

for only about half of the approximately 70 different nuclear

receptors that are now known. The receptors for unknown hor-

mone ligands are called orphan receptors. For example, the

receptor known as the retinoid X receptor (abbreviated RXR)

was an orphan until its ligand, 9- cis -retinoic acid (a vitamin A

derivative) was discovered. The significance of this receptor

will be described shortly.

Mechanism of Steroid Hormone Action

In general, steroid hormones exert their effects by entering their

target cells and binding to nuclear receptor proteins. Thus, they

influence their target tissue by stimulating genetic transcription.

This mechanism is known as the genomic action of steroids and

requires at least 30 minutes to work. Although this is the classi-

cally described mechanism of steroid action, it doesn’t explain

the observation that some effects occur within seconds to min-

utes. These effects are too fast to be explained by binding to

nuclear receptors and changes in genetic expression. This faster,

nongenomic action of steroids may occur in the cytoplasm of the

target cells and involve the activation of second-messenger sys-

tems, similar to the way polar hormones regulate their target cells

(discussed shortly). The genomic actions of steroids are better

established, and so only the genomic effects of steroid hormones

will be described in this section.

In the classic, genomic mechanism of steroid hormone

action, the receptors for the steroid hormones are located in

the cytoplasm before the steroid arrives. Depending on the ste-

roid and the tissue, however, unbound steroid receptors may be

located in the nucleus as well. (The particular distribution of

the receptor between the cytoplasm and nucleus varies.) When

the cytoplasmic receptors bind to their specific steroid hormone

ligands, they translocate (move) to the nucleus. Once in the

nucleus, the steroid hormone-receptor protein complexes bind

to specific DNA sequences called hormone response elements

in the regulatory regions of target genes ( fig. 11.5 ).

As illustrated in figure  11.5 , the hormone-response element

of DNA consists of two half-sites, each six nucleotide bases long,

separated by a three-nucleotide spacer segment. One steroid recep-

tor, bound to one molecule of the steroid hormone, attaches as a

single unit to one of the half-sites. Another steroid receptor, bound

to another steroid hormone, attaches to the other half-site of the

hormone-response element. The process of two receptor units com-

ing together at the two half-sites is called dimerization ( fig. 11.5 ).

Because both receptor units of the pair are the same, the steroid

receptor is said to form a homodimer. (The situation is different

for the nonsteroid family of receptors, as will be described.) Once

dimerization has occurred, the activated nuclear hormone recep-

tor stimulates transcription of particular genes, and thus hormonal

regulation of the target cell (see fig. 11.4 ).

Even this classical, genomic mechanism of steroid hormone

action is an oversimplification. For example, there are drugs

including enzyme proteins that change the metabolism of the

target cell.

Each nuclear hormone receptor has two regions, or domains:

a ligand (hormone)-binding domain and a DNA- binding domain

( fig. 11.5 ). The receptor must be activated by binding to its hor-

mone ligand before it can bind to a specific region of the DNA,

which is called a hormone-response element. This is a short

DNA span, composed of characteristic nucleotide bases, located

adjacent to the gene that will be transcribed in response to the

hormone-activated nuclear receptor.

The nuclear receptors are said to constitute a superfam-

ily composed of two major families: the steroid family and

the thyroid hormone ( or nonsteroid) family. In addition to the

receptor for thyroid hormone, the latter family also includes

the receptors for the active form of vitamin D and for retinoic

acid (derived from vitamin A, or retinol). Vitamin D and reti-

noic acid, like the steroid and thyroid hormones, are lipophilic

molecules that play important roles in the regulation of cell

function and organ physiology.

Figure 11.5 Receptors for steroid hormones.

( a ) Each nuclear hormone receptor protein has a ligand-binding

domain, which binds to a hormone molecule, and a DNA-binding

domain, which binds to the hormone-response element of DNA.

( b ) Binding to the hormone causes the receptor to dimerize on

the half-sites of the hormone-response element. This stimulates

genetic transcription (synthesis of RNA).

DNA

Steroid
hormone
Receptor protein
for steroid hormone

Hormone-

response

element

Ligand-binding
domain

DNA-binding
domain

(a)

(b)

Half-sites

Target gene

DNA

Dimerization of receptor

Genetic transcription

Steroid

hormone

Steroid

hormone

H

H H

mRNA