Biology Reference
In-Depth Information
the phenotype of an inactive V
2
R, which translates into the inability of the
kidneys to reabsorb water and hence, uncontrollable water loss in the urine,
that is, “diabetes insipidus.”
Of note, another naturally occurring polymorphism, resulting in substi-
tution of either Cys or Leu in the place of Arg137 of the human V
2
R, causes
a different clinical syndrome, the “nephrogenic syndrome of inappropriate
antidiuresis” (NSIAD).
43
This substitution also leads to constitutive
b
arr-
dependent V
2
R endocytosis, but contrary to the Arg137His one, also
(somewhat paradoxically) results in constitutive V
2
R-stimulated cAMP
accumulation. This impairs the kidney's ability to excrete excess free water,
which most probably underlies NSIAD in afflicted carriers.
43
To sum up,
b
arrs can cause severe dysfunction of several naturally occurring V
2
R var-
iants in humans, simply by acting as classical desensitizers and mediators
of internalization/downregulation of the V
2
R, but doing so in an aberrantly
excessive (constitutive) manner. Thus,
b
arr inhibition in the kidneys of car-
riers of such V
2
R polymorphisms might be of therapeutic value in the treat-
ment of renal syndromes, such as NDI and NSIAD, which can directly and
detrimentally impact cardiovascular function and homeostasis in these indi-
viduals (
Table 12.1
).
4.3. Niacin receptor (GPR109A)
Niacin (nicotinic acid), despite recent trials challenging its clinical effective-
ness,
95
has been a very useful lipid-lowering drug for over 50 years. In can,
however, induce severe cutaneous flushing, a major adverse effect that sig-
nificantly limits its utility in hyperlipidemic patients.
96
Both the serum free
fatty acid lowering and the cutaneous blood flow/flushing-stimulating
actions of niacin are exerted via activation of its receptor, GPR109A, which
is a G
i/o
-protein-coupled receptor.
97,98
In mice and humans, GPR109A has
been shown to activate G
i/o
protein signaling, leading to a decrease in plasma
triglycerides, a major risk factor for atherosclerosis and cardiovascular dis-
ease, and simultaneously to stimulate cytosolic phospholipase A
2
(
c
PLA
2
),
an important proinflammatory enzyme, which results in the production
and secretion of the vasodilatory prostaglandin D
2
(PGD
2
).
97,98
It is this pro-
duction of PGD
2
that underlies the adverse effect of flushing with niacin
treatment. Recently, it was demonstrated that
b
arr1, although dispensable
for the beneficial effects of niacin on free fatty acid lowering, promotes
the niacin-related flushing, as measured by perfusion of the ventral ear of
mice.
44
The underlying mechanism appears to be GPR109A-induced
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