Biology Reference
In-Depth Information
docking, and fusion to membranes as well as vesicle movement along the actin
and tubulin networks. Together, Rabs control almost all aspects of vesicular
trafficking. The use of dominant negative forms and constitutively active
mutants has greatly helped in delineating the roles of each isoform in traffick-
ing of proteins in general but most importantly of 7TM receptors.
4.1. Colocalization of Rabs with receptors and
-arrestin
Over the years, Rab4, Rab5, Rab7, and Rab11 were shown to regulate
receptor endocytosis, their trafficking through the endosomal pathway, as
well as their targeting to lysosomes.
82
Several receptors were shown to col-
ocalize with Rabs in different intracellular compartments. For example,
internalized
b
2
-adrenergic receptors are present in Rab5a-positive endo-
somes after 15 min of agonist treatment.
83
Similar observations were
reported for the endothelin receptors and the AT
1
R.
24,84
It is through
the use of Rab mutants mimicking the inactive or active form that elucida-
tion of the endocytic and trafficking routes utilized by 7TM receptors were
identified. For example, expression of a dominant negative Rab5a mutant
was shown to inhibit trafficking of the AT
1
R to enlarged vesicular struc-
tures, without altering its internalization from the plasma membrane.
24
This
particular receptor directly bound this Rab isoform as well as Rab 4, 7, and
11.
85
Other receptors such as the
b
2
-adrenergic, the thromboxane A2, and
the prostacyclin receptor were all shown to bind Rab11.
24,86-88
It was reported that the AT
1
R/
b
-arrestin complex localized to Rab5
positive endosomes.
24
However,
b
-arrestin overexpression was also
reported to decrease colocalization of the platelet-activating factor receptor
with Rab7 in endothelial cells.
27
As discussed in
Chapter 4
, some 7TM
receptors (class B) have the ability to internalize along with
b
-arrestin while
others (class A) dissociate from the
b
-arrestin at the plasma membrane.
89
Therefore, binding of
b
-arrestin to a receptor impacts the intracellular route
an active receptor uses. One such example is the Apelin receptor. When
stimulated with Apelin-13, this 7TM receptor acts as a class A receptor
(internalization without
b
-arrestin) while Apelin-36 stimulation leads to
trafficking reminiscent of the class B family (internalization with
b
-arrestin).
Interestingly, both Apelin-13 and -36 stimulation promoted receptor inter-
nalization to Rab5 positive early endosomes. However, Apelin-13 internal-
ized receptors rapidly recycled back through a Rab4-dependent pathway,
while Apelin-36-stimulated receptors were targeted to lysosomes by
Rab7.
12
b
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