DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

946 receptors have limited distribution compared with the distribution
of EP 3
and EP 4
receptors.
FP A
and FP B
receptors couple via G q
–PLC–IP 3
to mobilize
cellular Ca 2+ and activate PKC. In addition, stimulation of FP activates
Rho kinase, leading to the formation of actin stress fibers,
phosphorylation of p125 focal adhesion kinase, and cell rounding.
The FP receptor is expressed in kidney, heart, lung, stomach, and
eye; it is most abundant in the corpus luteum, where its expression
pattern varies during the estrus cycle.
Leukotriene and Lipoxin Receptors. Several receptors for the LTs and
lipoxins have been identified (Peters-Golden and Henderson, 2007)
(Table 33–1). Two receptors exist for both LTB 4
(BLT 1
and BLT 2
)
and the cysteinyl leukotrienes (CysLT 1
and CysLT 2
). A receptor that
binds lipoxin, ALX, is identical to the fMLP-1 receptor; the nomenclature
now reflects LXA 4
as a natural and potent ligand (Chiang
et al., 2006).
Cell Signaling Pathways and Expression. Phylogenetic comparison
reveals two clusters of LT/lipoxin receptors: the chemoattractant
receptors (BLT 1
, BLT 2
, and ALX), which also contain the DP 2
receptor for PGD 2
, and the CysLT 1
and CysLT 2
receptors. All are
G protein–coupled receptors (GPCRs) and couple with G q
and other
G proteins (Table 33–1), depending on the cellular context. The
BLT 1
is expressed predominantly in leukocytes, thymus, and spleen,
whereas BLT 2
, the low-affinity receptor for LTB 4
, is found in spleen,
leukocytes, ovary, liver, and intestine. BLT 2
binds 12(S)- and 12(R)-
HETE with reasonable affinity, although the biological relevance of
this observation is not clear.
CysLT 1
binds LTD 4
with higher affinity than LTC 4
, while
CysLT 2
shows equal affinity for both LTs. Both receptors bind LTE 4
with low affinity. Activation of G q
, leading to increased intracellular
Ca 2+ , is the primary signaling pathway reported. Studies also have
placed G i
downstream of CysLT 2
. CysLT 1
is expressed in lung and
intestinal smooth muscle, spleen, and peripheral blood leukocytes,
whereas CysLT 2
is found in heart, spleen, peripheral blood leukocytes,
adrenal medulla, and brain.
Responses to ALX-receptor activation vary with cell type. In
human neutrophils, AA release is stimulated, whereas Ca 2+ mobilization
is blocked; in monocytes, LXA 4
stimulates Ca 2+ mobilization.
The ALX receptor is expressed in lung, peripheral blood
leukocytes, and spleen.
SECTION IV
INFLAMMATION, IMMUNOMODULATION, AND HEMATOPOIESIS
Other Agents. Other AA metabolites (e.g., isoprostanes, epoxyeicosatrienoic
acids, hepoxilins) have potent biological activities, and
there is evidence for distinct receptors for some of these substances.
Some isoprostanes appear to act as incidental ligands at the TP
(Audoly et al., 2000), which may be important in the pathology of
cardiovascular disease. Others activate the FP (Kunapuli et al., 1997).
Certain eicosanoids, most notably 15-deoxy-Δ 12,14 -PGJ 2
(15d-PGJ 2
),
a dehydration product of PGD 2
, have been reported as endogenous
ligands for a family of nuclear receptors called peroxisome
proliferator–activated receptors (PPARs) that regulate lipid metabolism
and cellular proliferation and differentiation. However, their
affinities for PPARs are significantly lower than for cell surface receptors,
raising doubt about the physiological relevance of the
ligand–receptor interaction. in vitro 15d-PGJ 2
can bind PPARγ, but
the quantities formed in vivo are orders of magnitude lower than those
necessary for PPAR activation (Bell-Parikh et al., 2003). Specific receptors
for the HETEs and EETs have been proposed but not yet isolated.
Endogenous Prostaglandins,
Thromboxanes, and Leukotrienes:
Functions in Physiological and
Pathological Processes
The widespread biosynthesis and myriad of pharmacological
actions of eicosanoids are reflected in their complex
physiology and pathophysiology. The development
of mice with targeted disruptions of genes regulating
eicosanoid biosynthesis and eicosanoid receptors has
revealed unexpected roles for these autacoids and has
clarified hypotheses about their function (Austin and
Funk, 1999; Narumiya and FitzGerald, 2001; Matsuoka
and Narumiya, 2007; Smyth and FitzGerald, 2009).
Platelets. Platelet aggregation leads to activation of membrane
phospholipases, with the release of AA and consequent eicosanoid
biosynthesis. In human platelets, TxA 2
and 12-HETE are the two
major eicosanoids formed, although eicosanoids from other sources
(e.g., PGI 2
derived from vascular endothelium) also affect platelet
function. A naturally occurring mutation in the first intracellular loop
of the TP receptor is associated with a mild bleeding diathesis and
resistance of platelet aggregability to TP agonists (Hirata et al.,
1994). The importance of the TxA 2
pathway is evident from the efficacy
of low-dose aspirin in the secondary prevention of myocardial
infarction and ischemic stroke. The total biosynthesis of TxA 2
, as
determined by excretion of its urinary metabolites, is augmented in
clinical syndromes of platelet activation, including unstable angina,
myocardial infarction, and stroke (Smyth et al., 2009). Deletion of
the TP receptor in the mouse prolongs bleeding time, renders
platelets unresponsive to TP agonists, modifies their response to collagen
but not to ADP, and blunts the response to vasopressors and the
proliferative response to vascular injury.
PGI 2
inhibits platelet aggregation and disaggregates preformed
clumps. Deficiency of the IP receptor in disease-free mice
does not alter platelet aggregation significantly ex vivo, although
increased responsiveness to thrombin was evident in a mouse
model of atherosclerosis (Smyth and FitzGerald, 2009). Augmented
biosynthesis of PGI 2
in syndromes of platelet activation serves to
constrain the effects platelet agonists, vasoconstrictors, and stimuli
to platelet activation. However, PGI 2
does limit platelet activation
by TxA 2
in vivo, reducing the thrombotic response to vascular injury
(Cheng et al., 2002). The increased incidence of myocardial infarction
and stroke in patients receiving selective inhibitors of COX-2,
most parsimoniously explained by inhibition of COX-2-dependent
PGI 2
formation, supports this concept (Grosser et al., 2006b).
Low concentrations of PGE 2
activate the EP 3
receptor, leading
to platelet aggregation (Fabre, 2001). Deletion of the EP 3
in mice
leads to an increased bleeding tendency and decreased susceptibility
to thromboembolism. Deletion of mPGES-1 did not affect thrombogenesis
in vivo, probably due to substrate rediversion and
augmented formation of PGI 2
(Cheng et al., 2006b).
Vascular Tone. Because of their short t 1/2
, prostanoids do not circulate
and generally are considered not to impact directly on systemic
vascular tone. They may, however, modulate vascular tone locally