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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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