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Desensitization
Endocytosis
Agonist
γ
γ
Dyn
P
GRK
Dyn
P
β
β
P
α
Clathrin
α
AP-2
G protein-dependant
signaling
Endosome
internalization
Recycling to
membrane
P
P
P
Degradation (proteasome)
P
Figure 11.1 Schematic representation of b-arrestin-dependent regulation of GPCR sig-
naling. In response to agonist stimulation, and considering the case of a monomeric
receptor, the GPCR conformational change leads to G protein activation and
G protein-dependent signaling, for example, mediated by adenylyl cyclase, cAMP,
and PKA. Subsequently, the GRK induced receptor phosphorylation and recruitment
of the multifunctional scaffolding protein, b-arrestin. The receptor/b-arrestin binding
prevents further G protein activation, producing desensitization. The receptor can then
be internalized via the formation of the receptor - protein complex: GPCR/b-arrestin/
AP2/Clathrin. Once receptor endocytosis is completed via the action of dynamin
(Dyn), the endosome is internalized and the complex disassembled. It can now be
degradated or recycled to membrane.
GPCR, arrestins act as direct mediators of cell signaling by scaffolding var-
ious signaling molecules such as kinases and phosphatases. Therefore, a defi-
ciency of one b -arrestin isoform can at the same time enhance the G protein-
mediated signaling while abolishing the b -arrestin-mediated component of
the signaling responses elicited by a given receptor.
Several neurotransmitters mediate their effects in the brain by activation
of GPCR. Furthermore, more than 90% of all non-olfactory GPCR are
expressed in the brain, 11 where they regulate multiple vital functions and
control mood. Here, we will provide an overview of recent research
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