Biology Reference
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therapeutic effects are thought to be mediated, at least in part, by a direct or
indirect inhibition of GSK3 activity.
64,65
In mouse models, the indirect inhi-
bition of GSK3 through AKT and
b
-arrestin 2 in response to lithium has
been confirmed. The indirect inhibition of GSK3 by lithium is mediated
by the disruption of the
b
-arrestin 2/AKT/PP2A protein complex, at least
in the striatum.
66
In
b
-arrestin 2-deficient mice, lithium fails to activate
AKT and inhibit GSK3 in the striatum, and does not produce the antide-
pressant and antimanic effects observed in control mice. The hypothesis that
lithium acts through
b
-arrestin 2/AKT/GSK3 modulation of dopaminergic
signaling is further supported by recent findings that the AKT1 isoform is
essential for behavioral regulation by lithium in mice.
67
More and more evi-
dence implicates AKT/GSK3 pathway modulation in the effects of
mood stabilizers such as valproic acid and lamotrigine.
68,69
All these mood
stabilizers decrease phosphorylation of GSK3 substrates.
70
Thus,
b
-arrestin
2-mediated regulation of the AKT/GSK3 pathway may be a general mech-
anism of action for a variety of chemically distinct mood stabilizers, and
targeting this pathway could be a pharmacologic approach for the treatment
of neurologic or psychiatric dopaminergic diseases.
45,52
3. ARRESTINS IN SEROTONERGIC NEUROTRANSMISSION
3.1. Generalities
Serotonin (5HT) is a neurotransmitter widely implicated in biological func-
tions such as circadian rhythm, food intake, pain, learning, mood, sexual
behaviors, aggressiveness, and anxiety. Except the third type of serotonergic
receptors (5-HT3R), all serotonergic receptors are GPCR and are widely
expressed throughout the central nervous system. Like other GPCR, sero-
tonergic receptors are modulated by arrestins, notably receptors 5HT2A,
5HT2C, and 5HT4.
71
Like the 5HT2A receptor, 5HT2C is expressed in
neurons
72
and is thought to be implicated in mental diseases such as schizo-
phrenia, anxiety, and depression (reviewed in Ref.
73
).
In humans, 5HT2A receptor activation is associated with hallucinations,
and all serotonergic hallucinogens have affinity for this receptor.
74-76
Dereg-
ulation of 5HT2A receptors has been shown in various mental health dis-
eases such as depression, suicide, and schizophrenia.
77
Both
b
-arrestin
isoforms and 5HT2A receptors are coexpressed in a population of cortical
pyramidal neurons, notably in intracellular vesicles where colocalization
of
b
-arrestin 1 and the receptor has been demonstrated.
78
In vivo
and
in vitro
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