b-Arrestins in the Central Nervous System - Progress in Molecular Biology and Translational Science - page 262

developed and used successfully for the study of the functions of GRK2 in
other neurotransmitter systems, 24 this approach remains to be applied to
the study of the role of GRK2 in DA receptor functions.
That being said, indirect evidence supports a role of GRK2 in DA
receptor regulation. For instance, alterations in GRK2 expression levels
have been reported in DA-related mood disorders and in response to phar-
macologic treatments in different in vivo systems. 25,26 Furthermore, lesions
of dopaminergic neurons in primates are followed by an increased expres-
sion of GRK2 that can be reversed by chronic levodopa treatment. 27
However, these data were not fully replicated in rodents 28 despite a mod-
ulation of GRK2 level by chronic or acute cocaine treatments. 29 There is
also evidence that the neuronal calcium sensor 1, a regulator of GRK2
activity, is involved in D2R desensitization. 25 Finally, evidence obtained
from mice lacking the fragile X mental retardation protein (FMRP) sug-
gests a role of GRK2 in the regulation of forebrain D1R. In this model,
the lack of an interaction between FMRP and GRK2 would result in
hyperphosphorylation and desensitization of D1R that can be normalized
following GRK2 inhibition. 30
Despite its lower expression levels, GRK3 is also expressed in CNS and
with a similar expression pattern as GRK2. 31,32 GRK3 expression can be
enhanced by dopaminergic stimulation and reduced by unpredictable
stress. 33,34 At the functional level, absence of GRK3 has been shown to
decrease locomotor responses to cocaine and to the nonselective DA recep-
tor agonist apomorphine. However, the molecular mechanism underlying
these effects has not yet been elucidated.
GRK6 is also ubiquitously expressed in the brain but is principally found
in the striatum and in the cell bodies from substantia nigra DA neurons. 31 In
striatum, GRK6 is highly expressed in DA sensitive medium spiny neurons
and in cholinergic interneurons. 35 Impaired desensitization of DA receptors
was shown in GRK6-deficient mice. These mice are also hyperresponsive in
tests of locomotor sensitivity to cocaine, amphetamine, and morphine
which all result in an exacerbation of dopaminergic neurotransmission. 35,36
Studies performed with this model also revealed that the absence of GRK6
results in higher G protein coupling of striatal D2R without affecting D1R.
This results in a greater locomotor response for direct D2R agonists and
a rise in the affinity for D2R agonists in the absence of GRK6. 35,37 This
suggests a GRK6-dependent regulation of postsynaptic striatal D2R

desensitization.