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GRK, GRK3 and GRK6 translocate to the membrane after CRF stimula-
tion in a HEK cell model and contribute to CRF
1
receptor desensitiza-
tion.
149,150
Reducing GRK3 expression reduces CRF
1
receptor
desensitization,
150
while GRK3 overexpression in HEK cells promotes a
more rapid desensitization.
148
Contrary to CRF
2
, the extreme
C-terminus of the CRF
1
receptor contains a type 1 PDZ domain. Consid-
ering that PDZ domains can be phosphorylated by GRK or bind to PSD-95
and other modulatory proteins, its presence introduces another potential
element of response modulation.
151
6.3. Arrestins and CRF receptor internalization
CRF
1
receptors are rapidly activated and phosphorylated in the presence of
agonist. In HEK cells and mouse cortical neurons, the recruitment of
b
-arrestin 2 is more efficient than
b
-arrestin 1.
152,153
Truncating the
CRF
1
receptor C-terminus at Ser
386
inhibits
b
-arrestin 2 translocation to
the membrane, but truncating it at Ser
412
does not.
153
Because reducing
GRK3 expression impairs CRF
1
receptor desensitization, the phosphoryla-
tion site that most efficiently induces
b
-arrestin recruitment may be prefer-
entially phosphorylated by this GRK.
149,154
Urocortin neuropeptide 2 (UCN2) strongly activates CRF
2A
receptors
in human retinoblastoma Y79 cells.
155
The efficiency with which CRF
2
receptors (CRF
2A
and CRF
2B
) desensitize varies with different agonists.
While UCN2 induces rapid and strong CRF
2
receptor desensitization,
UCN3 and CRF are less efficient.
154
As with the CRF
1
receptor, CRF
2B
receptors efficiently recruit
b
-arrestins. But unlike CRF
1
receptors, CRF
2
receptor regulation is more dependent on the
b
-arrestin 1 isoform, since
decreasing cellular levels of
b
-arrestin 1 by siRNA reduces UNC2-induced
desensitization and internalization to a greater degree than silencing
b
-arrestin 2.
154
7. OTHER
b
-ARRESTIN-DEPENDENT BEHAVIOR
7.1. Cannabinoid receptors
Studies indicate that
b
-arrestin negatively regulates cannabinoid CB
1
recep-
tor functions.
156
D
9
-Tetrahydrocannabinol (
D
9
-THC) and CP55,940, two
CB
1
receptor agonists, induce antinociception and decrease in body temper-
ature in mice. While the response to
D
9
-THC is enhanced in
b
-arrestin 2
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