Page 16 - Color Atlas Of Pathophysiology (S Silbernagl Et Al, Thieme 2000)

Abnormalities of Intracellular Signal Transmission
As a rule, hormones do not influence cell func- [RH]) and statins (release-inhibiting hormones
tions directly, but via secondary intracellular [RIH]), glucagon, parathyroid hormone (PTH),
signals. This signal transmission is disrupted calcitonin, adiuretin ([ADH] V 2 receptors), gas-
in some diseases and can be influenced by cer- trin, secretin, vasoactive intestinal peptide
tain drugs and toxins. (VIP), oxytocin, adenosine (A 2 receptor), sero-
Some hormones bind to receptors of the tonin (S 2 receptor), dopamine (D 1 receptor),
cell membrane (→ A1–3). Usually through histamine (H 2 receptor), and to some extent
mediation of guanine nucleotide-binding pro- the prostaglandins.
teins (G proteins), the hormone–receptor in- Some peptide hormones and neurotrans-
teraction causes the release of an intracellular mitters, for example, somatostatin, adenosine
second messenger which transmits the hor- (A 1 receptor), dopamine (D 2 receptor), seroto-
monal signal within the cell. A given hormone nin (S 1α ), angiotensin II, and acetylcholine (M 2
can cause different intracellular second mes- receptor), act by inhibiting AC and thus re-
sengers to be formed, depending on the target ducing the intracellular cAMP concentration,
via an inhibiting G protein (G i ) (→ A2). Some
cell and receptor. Abnormalities can occur if,
Fundamentals for example, the number of receptors is reduced hormones can, by binding to different recep-
tors, either increase the cAMP concentration
(e.g., down-regulation in persistently high hor-
(epinephrine: β-receptor; dopamine: D 1 recep-
mone concentrations), the receptor’s affinity
tor), or reduce it (epinephrine: α 2 -receptor;
for the hormone is reduced, or coupling to the
(→ A; receptor defects).
The cAMP signaling cascade can be influ-
1 intracellular signaling cascade is impaired dopamine: D 2 receptor).
The so-called large, heterotrimeric G pro- enced by toxins and drugs, namely cholera tox-
teins consist of three subunits, namely α, β, in from Vibrio cholerae, the causative organ-
and γ. When the hormone binds to the recep- ism of cholera, and other toxins prevent the
tor, guanosine 5′-triphosphate (GTP) is bound deactivation of the α s subunit. The result is
to the α subunit in exchange for guanosine 5′- the uncontrolled activation of AC and subse-
–
diphosphate (GDP), and the α subunit is then quently of cAMP-dependent Cl channels, so
released from the β subunit. The α subunit that unrestrained secretion of sodium chloride
that has been activated in this way is then in- into the gut lumen causes massive diarrhea
activated by dephosphorylation of GTP to GDP (→ p.150). Pertussis toxin from Hemophilus
(intrinsic GTPase) and can thus be re-associ- pertussis, the bacillus that causes whooping-
ated with the β-γ subunits. cough (pertussis), blocks the G i protein and
Numerous peptide hormones use cyclic thus raises, among others, the cAMP concen-
adenosine monophosphate (cAMP) as second tration (disinhibition of AC). Forskolin directly
messenger in such a way that, mediated by a stimulates AC, while xanthine derivatives, for
stimulating G protein (G s ), adenylyl cyclase example, theophylline, inhibit phosphodies-
(AC) is activated and thus more cAMP is terase and thus the breakdown of cAMP, which
formed (→ A1). cAMP activates protein kinase also leads to an increase in cAMP concentra-
A (PKA), which phosphorylates, among others, tion (→ A4). The xanthine derivatives are used
enzymes and transport molecules. cAMP can therapeutically, among other drugs, to cause
also be involved in gene expression via PKA the bronchial musculature to dilate in asthma
and phosphorylation of a cAMP-responsive by raising the cAMP concentration.
element-binding protein (CREB). cAMP is con- In addition to cAMP, cyclic guanosine
verted to noncyclic AMP by intracellular phos- monophosphate (cGMP) serves as an intracel-
phodiesterases and the signal thus turned off. lular messenger (→ A5). cGMP is formed by
The following hormones act via an increase in guanylyl cyclase. cGMP achieves its effect pri-
intracellular cAMP concentration: corticotro- marily via activation of a protein kinase G
pin (ACTH), lutotropin (luteinizing hormone (PKG). Atrial natriuretic factor (ANF) and nitric
6 [LH]), thyrotropin (TSH), prolactin, somatotro- oxide (NO), among others, also act via cGMP.
pin, some of the liberines (releasing hormones Other intracellular transmitters are 1,4,5-
Silbernagl/Lang, Color Atlas of Pathophysiology © 2000 Thieme
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