b-Arrestins in the Central Nervous System - Progress in Molecular Biology and Translational Science - page 269

3.4. Alternative pathways
The activation of 5HT2C receptors also leads to ERK1/2 activation in dif-
ferent cell lines 92,93 via both b -arrestin-dependent and -independent pro-
cesses. 93 Activation of the ERK1/2 pathway by 5HT is dependent on
5HT2A receptor and b -arrestin in a MEF cellular model as well as in vivo. 91
In the mouse frontal cortex, serotonin and the 5HT2A receptor selective
agonist DOI both induce ERK1/2 activation, but in the absence of
b -arrestin 2 only DOI activates the pathway. Furthermore, the serotonin
receptor-mediated activation of the AKT pathway via SRC and PI3 kinase
is also b -arrestin dependent in cultured cortical neurons and in vivo 90
( Fig. 11.2 ).
It has also been shown that GRK5 is a direct interaction partner of 5HT4
receptors and a negative regulator of the ERK1/2 signaling pathway in
response to serotonergic stimulation 85 ( Fig. 11.2 ). In HEK cells and neurons,
overexpression of GRK5 inhibits G protein-independent signaling path-
ways, including activation of ERK1/2. GRK5 phosphorylates the Ser412
residue of b -arrestin 1, leading to simultaneous inhibition of receptor inter-
nalization and b -arrestin 1 binding to clathrin, which is dependent upon
Ser412 dephosphorylation. 94
4. ARRESTINS IN NORADRENERGIC
NEUROTRANSMISSION
4.1. Generalities
Epinephrine and norepinephrine (NE) neurotransmission is mediated pre-
dominantly by adrenergic receptors (AR). These endogenous catechol-
amines activate two classes of AR: a - and b -AR. All AR are GPCR, and
b -AR were the first metabotropic neurotransmitter receptors identified.
There are two subclasses of a -AR. While a 1 AR activation induces a slow
depolarization mediated by inhibition of K þ channels, activation of the
a 2 AR subclass induces a slow hyperpolarization. There are three subclasses
of b -AR: b 1 -, b 2 -, and b 3 AR, of which the b 1 - and b 2 AR are the major
species expressed in the brain. 95
Among a 2 AR, another subdivision has been made and we can distin-
guish three a 2 AR subtypes: a 2A , a 2B , and a 2C . All of these receptors are
coupled to G a i, and their activation leads to inhibition of AC and inhibition
of cAMP production. Conversely, b -AR are coupled to G a s proteins. The
activation of G a s leads to the activation of AC, generation of cAMP, and