Biology of Disease

Margin Note 7.1 G proteins

G proteins are so called because

they bind the guanyl nucleotides,

GDP and GTP. They are a diverse

group, ranging from small soluble

monomers to large multisubunit

membrane proteins. Their functions

are also wide ranging, from the

activities associated with numerous

hormones, to sense perception and

the nucleocytoplasmic transport

described in Chapter 16. However, all

are GTPases that can hydrolyze their

bound GTP to GDP

GTP protein

+

H 2 O

GDP protein*

+

Pi

The GDP portion can be exchanged

for a GTP. This alteration of the

nucleotide between the GTP–GDP

forms allows the protein to switch

between two conformations (Figure

7.9). The form with a bound GTP

is active (functional); the other has

GDP bound and is nonactive. Thus

G proteins provide on–off switches

in physiological systems as they

oscillate between the two forms.

*indicates a change in the conformation of the

protein (see also Figure 7.9)

they regulate the synthesis of proteins. For example, steroid hormones are

hydrophobic and lipid soluble and so diffuse directly through the plasma

membrane into the cytoplasm of target cells. Thyroid hormones enter their

target cells by facilitated diffusion. In the cytoplasm, steroid and thyroid

hormones bind to intracellular receptors forming hormone–receptor

complexes (Figure 7.10). The complex then interacts with the DNA of specific

genes in the nucleus to switch their transcription on or off, allowing or

preventing the production of appropriate mRNA molecules respectively. Thus

the cell’s production of proteins, such as enzymes, is regulated to produce a

physiological response to the hormone.

7.4 Causes of Endocrine Disorders

Endocrine disorders arise because a disruption to the endocrine system

causes decreased (hypofunction) or increased (hyperfunction) hormonal

activity or resistance to hormone action. There may be defects in synthesis

of the hormone due to an inherited deficiency of an enzyme required for

its synthesis. Inappropriate stimuli may impair the release of the hormone

or certain drugs may stimulate hormone release. Defects in the negative

feedback mechanism may cause abnormal hormone secretion. Faulty

inactivation or excretion of hormones in liver or renal diseases respectively

can increase hormone levels. Excessive hormone secretion can occur

ectopically from a nonendocrine source, such as a tumor. Even if correctly

synthesized and released, the target tissues may not recognize the hormone

because of a lack of receptors or because the receptors themselves are

nonfunctional. Disorders will also occur if the target cells do recognize the

hormone but there is a defect in the secondary messenger system responsible

for converting the hormonal signal to a physiological action.

In some autoimmune diseases (Chapter 5), antibodies are produced that

stimulate or destroy endocrine glands, as in Grave’s disease and autoimmune

thyroiditis respectively. The various causes underlying endocrine disorders

are summarized in Figure 7.11. A considerable number of endocrine disorders

have been described including disorders associated with the pituitary, thyroid,

pancreas, adrenal glands and the reproductive systems.

X]VeiZg,/ DISORDERS OF THE ENDOCRINE SYSTEM

&+) W^dad\nd[Y^hZVhZ

Figure 7.9 A small soluble G protein with bound (A) GDP and (B) GTP. In both cases the

nucleotide is shown in red. Note the difference in conformation between the two forms. PDB

files 1OIV and 1OIW respectively.

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