Arrestins as Regulators of Kinases and Phosphatases - Progress in Molecular Biology and Translational Science - page 132

of AKT and GSK3 b kinase activity by transiently inhibiting PP2A in the
signalsome complex. 58 PAR1 receptor activation also reportedly causes
rapid activation of AKT through an unknown arrestin2-dependent
mechanism. 68
Dopaminergic neurotransmission in the brain regulates behavioral
responses such as locomotor activity and neural reward mechanisms. Loss
of dopaminergic cells in the substantia nigra leads to a loss of locomotor con-
trol in Parkinson's disease. Conversely, D2 dopamine receptor antagonists are
effective neuroleptic drugs used in the treatment of schizophrenia and
attention-deficit hyperactivity disorder, which are thought to result from
excess dopaminergic neurotransmission. Several lines of evidence suggest that
arrestin-signaling complexes regulate dopamine-dependent behaviors.
Locomotor hyperactivity induced by the dopaminergic drug apomorphine,
a D2 receptor agonist, is reduced in arrestin3 knockout mice. 57 Similarly, the
hyperactivity displayed by dopamine-transporter knockout mice, which
results from increased synaptic dopamine concentration, is reduced when
DAT knockout mice are crossbred with arrestin3 knockouts, a paradoxical
result, since G protein-mediated responses would be enhanced by the
loss of arrestin-dependent desensitization. Themolecular basis of these effects
may lie in the scaffolding of PP2A-AKT-GSK3 by arrestin3. Amphetamine
treatment, which increases synaptic dopamine release, increases the
PP2A-AKT association in wild type, but not arrestin3 knockout mice,
suggesting that arrestins mediate the interaction. 57 Directly inhibiting
PP2A or GSK3 b also mimics the effect of arrestin3 knockout on hyperactive
locomotor activity in DAT knockout mice, suggesting that dopamine-
mediated activation of GSK3 b results fromPP2A-dependent AKT inhibition
that is scaffolded by arrestin3. 23
Arrestin3-PP2A-AKT scaffolds may underlie themechanismof action of
many antipsychotic drugs. Lithium, a mood stabilizer used in the treatment
of schizophrenia, modulates dopamine-dependent behavior in mice such as
horizontal activity. GSK3 b haploinsufficient mice exhibit augmented
lithium-induced antidepressant and anxiolytic effects compared to wild-type
animals, suggesting that lithium acts by inhibiting GSK3 b . Therapeutic con-
centrations of lithium disrupt the interaction between arrestin3, AKT, and
PP2A, relieving PP2A-mediated negative regulation of AKT, allowing it
to phosphorylate and inactivate GSK3 b . 57 The arrestin3-PP2A-AKT com-
plex requires magnesium, and lithium is thought to destabilize the complex
by competing for magnesium binding. The clinical efficacy of essentially
all other classes of antipsychotic drug correlates directly to their dopamine