Biology Reference
In-Depth Information
studies demonstrate an interaction between arrestins and the 5HT2A recep-
tor. Thus, the third intracellular domain of murine 5HT2A receptors inter-
acts with both b -arrestin 1 and 2. 78 These studies indicate a potential in vivo
role of b -arrestin 1 in 5HT2A receptor regulation and modulation in the
frontal cortex. In mental diseases, the level of b -arrestin 1 is reduced in lym-
phocytes of depressed patients, and the level of diminution is correlated with
the severity of symptoms. 79 In a reciprocal way, chronic treatment with anti-
depressant compounds such as imipramine, desipramine (DMI), and
fluvoxamine is associated with an augmentation of b -arrestin 1 expression
in the cortex and hippocampus in rat brains. 79
Elevation of 5HT in rodent brains via administration of
5-hydroxytryptophan (5HTP), or 5HT2A receptor activation in response
to hallucinogenic drugs, induces a characteristic behavior in control animals,
head twitch. 80,81 This serotonin-specific behavior can be observed follow-
ing an elevation of 5HT levels in the brain and is induced by administration
of the serotonin precursors, tyrptophan or 5HTP, inhibition of serotonin
reuptake by selective serotonin reuptake inhibitors, or inhibitors of seroto-
nin degradation like inhibitors of monoamine oxidase A inhibitors. 80 Con-
sidering this, it is not surprising that blockade of 5HT2A receptors is a critical
action underlying the antipsychotic potential of clozapine, risperidone, and
olanzapine compounds. 82
3.2. 5HT receptors and GRK
Serotonin receptor internalization is likely to be b -arrestin and GRK depen-
dent, as it was described for 5HT4 receptors associated with the stress
response. 83 Overexpression of GRK2 significantly diminished cAMP pro-
duction, suggesting a negative regulation of the receptor by GRK2. This
mechanism has been observed for different receptor variants expressed in
COS-7 cells,
including the 5HT4A, 5HT4B, 5HT4E, and 5HT4F
receptors. 84
3.3. Arrestins and 5HT receptor internalization
In HEK293 cells expressing 5HT4R, serotonin stimulation initiates the
recruitment of b -arrestin 1 and 2 to the plasma membrane and induces
receptor internalization. 85 After the serotonin stimulation, the recruitment
of b -arrestin 2 is dependent on phosphorylation by GRK2 of Ser/Thr
Search WWH ::




Custom Search