Biology Reference
In-Depth Information
be required for ET
A
receptor-dependent arterial smooth muscle cell migra-
tion in response to ET-1.
41
Given that this process underlies vascular rem-
odeling and occlusion, this finding might have important implications for
treatment of atherosclerosis and vascular (re)stenosis. Thus, it appears that
VSM cell
b
arr2 is instrumental not only in AngII/AT
1
R-dependent
VSM remodeling and vascular stenosis, but also in analogous ET-1/ET
A
receptor-dependent effects, which suggests that inhibiting vascular
b
arr2
signaling might be beneficial in treatment of vascular diseases, such as ath-
erosclerosis and post-PCI vessel restenosis (
Table 12.1
). Finally, ET recep-
tors play important roles in pulmonary vasculature, where they mediate
vasoconstriction and can contribute to pulmonary arterial hypertension.
91
Therefore,
b
arrs, as either ET receptor desensitizers or signal transducers,
might be involved in the pathophysiology of this disease as well.
4.2. Vasopressin receptors
Vasopressin is another important hormone for the cardiovascular system that
exerts its effects through two different GPCR types, V
1
and V
2
.
92
V
1
vaso-
pressin receptor (V
1
R) is a G
q/11
-coupled receptor located in VSM cells,
where it promotes vasoconstriction and thus raises blood pressure, whereas
V
2
RisaG
s
protein-coupled receptor, located mainly in the renal tubular
epithelial cells of the distal nephron, where it regulates renal water
reabsorption.
92
Both vasopressin receptor types interact with
b
arrs
in vitro
.
The V
2
R is a classic example of a Class B GPCR in terms of its
b
arr-
dependent endocytosic properties, that is, it binds and internalizes with both
b
arrs equally, and its interaction with
b
arrs is strong and long-lasting.
93
So far, the effects of
b
arrs on vasopressin receptor signaling relevant to
the cardiovascular system have been studied only in the context of naturally
occurring single nucleotide polymorphisms in the human V
2
R gene. One
such polymorphism results in the substitution of Arg for His at position 137
of the encoded receptor protein.
42
This mutation, located in the second
intracellular loop of the receptor, severely affects V
2
R agonist-promoted
receptor desensitization and downregulation. It was initially identified as a
“loss-of-function” V
2
R polymorphism, strongly associated with the clinical
syndrome of nephrogenic diabetes insipidus (NDI) in afflicted carriers.
94
Subsequently, at the molecular level, it was found to cause constitutive
GRK-mediated receptor phosphorylation followed by unrestrained
b
arr-
mediated V
2
R desensitization, internalization, and loss of responsiveness
to circulating vasopressin.
42
Thus, this molecular abnormality produces
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