Biology Reference
In-Depth Information
Abstract
b-Arrestins 1 and 2 are ubiquitously expressed proteins that play a dual role in G protein-
coupled receptor (GPCR) signaling. On the one hand, arrestins are central to the termi-
nation of G protein-mediated receptor signaling and subsequent clathrin-dependent
internalization. On the other hand, these proteins act as molecular scaffolds for
G protein-independent GPCR signaling. This review provides an overview of how these
dual functions of arrestins contribute to the biological outcomes associated to the acti-
vation of different brain GPCR. It also explores recent evidence suggesting how the dual
function of arrestins can lead to the development of more selective pharmacological
approaches for the treatment of central nervous system disorders such as chronic pain,
bipolar disorder, major depression, and schizophrenia. Development of such
approaches may lead to new drugs having better clinical efficacy and lesser side effects.
1. INTRODUCTION: ARRESTINS AND GRK IN THE
CENTRAL NERVOUS SYSTEM
Arrestins and G protein receptor kinases (GRK) are major players in
cell signaling by G protein-coupled receptors (GPCR), the most abundant
membrane receptor class.
1-4
Arrestins serve as scaffold proteins. Of the four
arrestin proteins, isoforms 1 and 4 are predominant in the visual system,
whereas arrestins 2 and 3 are ubiquitously expressed. In the adult brain,
arrestin 2, classically named
b
-arrestin 1, is 10-20 times more abundant at
the protein level despite only a two-fold difference in mRNA expression
over arrestin 3, also known as
b
-arrestin 2.
5
Although expression of both
isoforms is distributed throughout the brain,
b
-arrestin 2 is the predominant
isoform in limbic areas such as the hypothalamus and extended amygdala.
Therefore, the hypothalamus is the only major brain area where the
b
-arrestin 2 mRNA level is comparable to that
b
-arrestin 1.
5
As hinted by their name, arrestins are major components of a protein
complex shutting down G protein-mediated signaling by GPCR
(
Fig. 11.1
). Following agonist binding, GPCR activation results in activa-
tion of G proteins, which regulate different downstream effectors through
various combinations of G
a
and G
bg
subunits.
b
-Arrestins are recruited
to the receptor following its phosphorylation by GRK to trigger clathrin-
mediated receptor internalization.
6-10
Arrestin recruitment to phosphory-
lated GPCR inhibits signal transduction by preventing further receptor
coupling to G proteins. Following, or in parallel to, their action on
G protein-mediated signaling, there is evidence that, at least for some
Search WWH ::
Custom Search