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

are typical heptahelical GPCRs. Manning and co-workers
(1999) synthesized novel hypotensive vasopressin
peptide agonists that do not interact with V 1a
, V 1b
, or V 2
receptors and may stimulate a putative vasopressin
vasodilatory receptor.
Two additional putative receptors for vasopressin
have been cloned. A vasopressin-activated
Ca 2+ -mobilizing receptor with one transmembrane
domain binds vasopressin and increases intracellular
Ca 2+ (Serradeil-Le Gal et al., 2002). A dual AngIIvasopressin
heptahelical receptor activates adenylyl
cyclase in response to both AngII and vasopressin
(Serradeil-Le Gal et al., 2002). The physiological roles
of these putative vasopressin receptors are unclear.
V 1
Receptor-Effector Coupling. Figure 25–19 summarizes
the current model of V 1
receptor-effector coupling.
Vasopressin binding to V 1
receptors activates the
AVP
G q
-PLC-IP 3
pathway, thereby mobilizing intracellular
Ca 2+ and activating PKC, ultimately causing biological
effects that include immediate responses (e.g., vasoconstriction,
glycogenolysis, platelet aggregation, and
ACTH release) and growth responses in smooth muscle
cells. Other effects of V 1
-receptor activation may be
mediated by stimulation of small G proteins, activation
of PLD and PLA 2
, and activation of V 1
-sensitive
Ca 2+ influx. Some effects of V 1
-receptor activation
are secondary to synthesis of prostaglandins and
epoxyeicosatrienoic acids (Chapter 33).
V 2
Receptor-Effector Coupling. Principal cells in renal
collecting duct have V 2
receptors on their basolateral
membranes that couple to G S
to stimulate adenylyl
cyclase activity (Figure 25–20) when vasopressin binds
to V 2
receptors. The resulting increase in cellular cyclic
AMP and PKA activity triggers an increased rate of
AVP
705
CHAPTER 25
Cell
membrane
Proteins
AVP
V 1
β γ
α q
+
PLC β
Interstitial space
DAG PKC
Proteins
IP 3
Ca 2+
Ca 2+
Calcisome
Proteins
Ca 2+
Vasoconstriction
Glycogenolysis
Platelet aggregation
ACTH Release
+ +
Immediate
Cell
responses
growth
Figure 25–19. Mechanism of V 1
receptor-effector coupling. Binding of 8-arginine vasopressin (AVP) to V 1
vasopressin receptors (V 1
)
stimulates several membrane-bound phospholipases. Stimulation of the G q
-PLC β
pathway results in IP 3
formation, mobilization of
intracellular Ca 2+ , and activation of PKC. Activation of V 1
receptors also causes influx of extracellular Ca 2+ by an unknown mechanism.
PKC and Ca 2+ /calmodulin-activated protein kinases phosphorylate cell-type-specific proteins leading to cellular responses. A
further component of the AVP response derives from the production of eicosanoids secondary to the activation of PLA 2
; the resulting
mobilization of arachidonic acid (AA) provides substrate for eicosanoid synthesis by the cyclooxygenase (COX) and lipoxygenase
(LOX) pathways, leading to local production of prostaglandins (PG), thromboxanes (TX), and leukotrienes (LT), which may activate
a variety of signaling pathways, including those linked to G S
and G q
. Biological effects mediated by the V 1
receptor include vasoconstriction,
glycogenolysis, platelet aggregation, ACTH release, and growth of vascular smooth muscle cells. The effects of vasopressin
on cell growth involve transcriptional regulation by the FOS/JUN AP-1 transcription complex.
PO 4
DAG
Proteins
AP-1
PA
Cell growth
PLD
AVP
V 1
?
?
+ +
AA
COX LOX
PG, TX LT
Modulation of
cellular
signaling
PLA 2
REGULATION OF RENAL FUNCTION AND VASCULAR VOLUME