Biology Reference
In-Depth Information
in mammalian tissue and are known to contribute to the uncoupling of many
GPCRs from heterotrimeric G proteins.
10,11
For many years,
b
-arrestin
actions were thought to be limited to the desensitization and internalization
processes of GPCRs.
12-15
However, over the past several years,
b
-arrestins
have emerged as one of the key players involved in the regulation of multiple
facets of GPCR function; hence, they have evolved as multifunctional cel-
lular mediators.
16
Besides the well-known participation of
b
-arrestins in
receptor desensitization, due to their ability to uncouple GPCR/G protein
complexes,
b
-arrestins have also been identified as signal scaffolding proteins
as they contain specific interaction sites for various signaling as well as acces-
sory molecules.
12,16,17
Consequently,
b
-arrestins not only have the capacity
to regulate GPCR desensitization, they also control a vast array of additional
cellular functions including cell signaling as well as membrane, cytosolic, and
nuclear-associated trafficking of GPCRs.
16
Intense research has been con-
ducted to identify the kinetics of
b
-arrestin binding, as well as the molecular
determinants that dictate whether
b
-arrestins bind to a given GPCR and/or
subsequently regulate GPCR activity at multiple steps within the GPCR life
cycle. This chapter will focus on the current understanding of how and to
what extent
b
-arrestins control GPCR desensitization, sequestration, and
vesicular trafficking.
2. ARRESTINS IN GPCR DESENSITIZATION
Receptor desensitization represents an important physiological pro-
cess that prevents GPCRs from overstimulation due to prolonged agonist
exposure by signal attenuation or termination.
2,3
The classical model of
GPCR desensitization involves three processes: (1) receptor phosphoryla-
tion and subsequent uncoupling of the receptor from its cognate
G protein, (2) receptor sequestration (internalization) to intracellular com-
partments, and (3) downregulation. Desensitization is typically elicited by
three classes of regulatory molecules: (1) second messenger-dependent pro-
tein kinases, (2) G protein-coupled receptor kinases (GRKs), and (3)
b
-arrestins.
3,11
Second messenger-dependent protein kinases, such as pro-
tein kinase A and C, that mediate heterologous desensitization, phosphor-
ylate GPCRs at specific consensus sequences within intracellular loops or
carboxyl terminal domains that prevent G protein coupling. However, sec-
ond messenger-dependent protein kinases do not discriminate between
inactive and agonist-activated GPCRs. Hence, they prevent the activation
of GPCRs that have never been exposed to agonists as well as receptors that
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