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

can couple to both elevation of intracellular calcium and a decrease
in cyclic AMP. The DP 2
receptor is an exception and is unrelated
to the other prostanoid receptors; rather, it is a member of the
formyl-methionyl-leucyl-phenylalanine (fMLP)-receptor superfamily
(Table 33–1).
TP α
and TP β
receptors couple via G q
and several other G
proteins, to activate the PLC–IP 3
–Ca 2+ pathway (Figure 33–4).
Activation of TP receptors also may activate or inhibit adenylyl
cyclase via G s
(TP α
) or G i
(TP β
), respectively, and signal via G q
,
G 12/13
, and G 16
, to stimulate small G protein–signaling pathways,
including ERK and Rho. TP is expressed in platelets, vasculature,
lung, kidney, heart, thymus, and spleen. The TP α
apparently is the
sole isoform expressed in platelets (see Smyth and FitzGerald,
2009). Recognized differences between the splice variants are limited
to G protein activation and receptor regulation in heterologous
in vitro expression systems.
IP couples with G s
to stimulate adenylyl cyclase activity. It is
expressed in many tissues and cells, including human kidney, lung,
spine, liver, vasculature, and heart.
IP
EP 2
“Relaxant” “Contractile” “Inhibitory”
EP 4
DP 1
+
DP 1
also couples with adenylyl cyclase through G s
. It is the
least abundant of the prostanoid receptors, with expression in mouse
ileum, lung, stomach, and uterus. In humans, several subtypes of
leukocytes express DP 1
, including eosinophils, basophils, monocytes,
dendritic cells, and T lymphocytes. DP 1
also is expressed in
the central nervous system (CNS), where it appears to be limited
specifically to the leptomeninges and the vasculature. DP 2
couples
with the G q
–PLC–IP 3
pathway to increase intracellular Ca 2+ (Figure
33-4). Its mRNA is found in many human tissues (brain, heart,
thymus, spleen, liver, and intestine). DP 2
is expressed on mast cells,
T lymphocytes (Th2 but not Th1), basophils, and eosinophils (Kim
and Luster, 2007).
EP 2
and EP 4
receptors activate adenylate cyclase via G s
. The
EP 2
receptor is expressed at much lower levels in most tissues and
can be induced in response to inflammatory stimuli, suggesting distinct
roles for these two G s
-coupled EP receptors. The EP 1
receptor,
via an unclassified G protein, can activate the PLC–IP 3
–Ca 2+ pathway.
All human EP 3
isoforms can activate G i
to inhibit adenylyl cyclase;
however, certain isoforms can activate G s
or G 12/13
. EP 1
and EP 2
α s α 12/13 α 16 α q α i
β γ β γ β γ β γ β
RhoGEF
TP
EP 1
+ +
PLC-β
FP
EP 3
**
fMLP receptor
family
γ
DP 2
945
CHAPTER 33
LIPID-DERIVED AUTACOIDS: EICOSANOIDS AND PLATELET-ACTIVATING FACTOR
Rho activation
Ca 2+
Biological Effects
cAMP
+
Adenylyl
cyclase
–
Figure 33–4. Prostanoid receptors and their primary signaling pathways. Prostanoid receptors are members of the heptaspanning,
G protein–coupled receptor superfamily. The terms “relaxant,” “contractile,” and “inhibitory” refer to the phylogenetic characterization
of their primary effects. **All EP 3
isoforms couple through G i
, but some can also activate G s
or G 12/13
pathways. See the text for
additional details.