b-Arrestins in the Central Nervous System - Progress in Molecular Biology and Translational Science - page 261

examining the impact of the dual function of arrestins in relation to specific
neurotransmitter systems. In doing so, we will concentrate mostly on work
conducted directly in the brain tissue using various animal models of altered
neurotransmission or arrestin expression.
2. ARRESTINS AND GRK IN DOPAMINERGIC
NEUROTRANSMISSION
2.1. Generalities
Dopamine (DA) neurotransmission is implicated in a wide range of func-
tions such as locomotion, cognition, emotions, neuroendocrine control,
and reward. 12 It can thus be expected that abnormal DA neurotransmission
is associated with several neurological and psychiatric disorders including,
most notably, Parkinson's disease, Huntington's disease, and schizophrenia.
DA signaling is mediated by five DA receptors separated in two families on
the basis of their effect on cAMP production. Class 1 DA receptors consist of
the D1 and D5 DA receptors (D1R and D5R) that stimulate the activity of
adenylate cyclase (AC) and the production of cAMP 13,14 by coupling to G a s
subunit containing G proteins. Class 2 DA receptors are the D2R, D3R, and
D4R receptors, which are coupled to G a i and inhibit AC. In the striatum,
these two classes of receptors are present in distinctive neuronal populations
with a high level of segregation and their distinct projections distinguish
between the direct and indirect striatonigral pathways. 15,16 Nevertheless,
a small population of neurons expresses both D1 and D2 receptors, which
may change the signaling properties of these receptors following the forma-
tion of receptor heterodimers. 17,18
2.2. DA receptors and GRK
Various studies have suggested the importance of GRK, notably GRK2,
for DA receptor regulation in vitro. 19-23 Mice lacking one allele of the
GRK2 gene display a slight enhancement of responsiveness to cocaine,
which increases DA tone by preventing its reuptake. This is suggestive
of a role for GRK2 in the regulation of DA receptor desensitization in vivo .
However, direct evidence for this is not currently available. A major reason
is the embryonic lethality of GRK2 knockout mice, which has precluded
the definitive examination of the role of this kinase in the regulation of DA
receptor functions in vivo . While conditional GRK2 knockouts have been