132
Chapter 5
are generated in many kinds of cells in response to an extracel-
lular signal.
The synthesis of eicosanoids begins when an appropriate
stimulus—hormone, neurotransmitter, paracrine agent, drug,
or toxic agent—binds its receptor and activates an enzyme,
phospholipase A
2
,
in the plasma membrane of the stimulated
cell. As shown in Figure 5–12, this enzyme splits off arachidonic
acid from the membrane phospholipids, and the arachidonic
acid can then be metabolized by two pathways. One pathway
is initiated by an enzyme called
cyclooxygenase (COX)
and
leads ultimately to formation of the cyclic endoperoxides, pros-
taglandins, and thromboxanes. The other pathway is initiated
by the enzyme
lipoxygenase
and leads to formation of the
leukotrienes. Within both of these pathways, synthesis of the
various specifi c eicosanoids is enzyme-mediated. Thus, beyond
phospholipase A
2
, the eicosanoid-pathway enzymes expressed
in a particular cell determine which eicosanoids the cell synthe-
sizes in response to a stimulus.
Each of the major eicosanoid subdivisions contains more
than one member, as indicated by the use of the plural in
referring to them (prostaglandins, for example). On the basis
of structural differences, the different molecules within each
subdivision are designated by a letter—for example, PGA and
PGE for prostaglandins of the A and E types—which then
may be further subdivided—for example, PGE
2
.
Once they have been synthesized in response to a stimu-
lus, the eicosanoids may in some cases act as intracellular mes-
sengers, but more often they are released immediately and act
locally. Thus, the eicosanoids are usually categorized as para-
crine and autocrine agents. After they act, they are quickly
metabolized by local enzymes to inactive forms. The eico-
sanoids exert a wide array of effects, particularly on blood ves-
sels and in infl ammation. Many of these will be described in
future chapters.
Because arachidonic acid transduces a signal from a mes-
senger and its receptor into a cellular response (production
and secretion of eicosanoids), it is sometimes considered a sec-
Cytosolic Ca
2+
Inactive
calmodulin
Active Ca
2+
-
calmodulin
Ca
2+
entry via plasma membrane Ca
2+
channels
and/or
Ca
2+
release from endoplasmic reticulum
Inactive
calmodulin-dependent
protein kinase
Active
calmodulin-dependent
protein kinase
+ ATP
Protein-PO
4
+ ADP
CELL’S RESPONSE
Protein
Extracellular fluid
Plasma membrane
Intracellular fluid
Receptor
Begin
First
messenger
Second
messenger
Figure 5–11
Calcium, calmodulin, and the calmodulin-dependent protein kinase
system. (There are multiple calmodulin-dependent protein kinases.)
Table 5–4 summarizes the mechanisms for increasing cytosolic
calcium concentration.
Receptor
Cyclic endoperoxides
Arachidonic acid
Membrane phospholipid
Cyclooxygenase
pathway
Vascular actions,
inflammation
Blood clotting
and other
vascular actions
Mediate allergic and
inflammatory reactions
Lipoxygenase
pathway
Prostaglandins
Leukotrienes
Thromboxanes
Phospholipase A
2
Begin
First
messenger
Figure 5–12
Pathways for eicosanoid synthesis and some of their major functions.
Phospholipase A
2
is the one enzyme common to the formation
of all the eicosanoids; it is the site at which stimuli act. Anti-
infl ammatory steroids inhibit phospholipase A
2
. The step mediated
by cyclooxygenase is inhibited by aspirin and other nonsteroidal
anti-infl ammatory drugs (NSAIDs). There are also drugs available
that inhibit the lipoxygenase enzyme, thus blocking the formation
of leukotrienes. These drugs may be helpful in controlling asthma,
in which excess leukotrienes have been implicated in the allergic and
infl ammatory components of the disease.
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