Biology Reference
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clusters on the receptor C-terminal tail.
84
In humans, 9 5HT4 receptor var-
iants are produced by alternative splicing. These variants differ in their
C-terminal regions. The pharmacologic properties seem to be shared among
the variants, but the downstream signaling and regulation of these receptors
can be different.
84,86
5HT4 receptors can be internalized and desensitized in
a conventional way via GRK and
b
-arrestin. Nevertheless, 5HT4A and
5HT4B signaling may depend on different internalization processes
according to their different subcellular distribution.
87
5HT2A receptors can also be internalized via a
b
-arrestin-dependent
pathway. Studies using HEK293 cell lines demonstrate colocalization of
5HT2A receptors and
b
-arrestin, and membrane recruitment of both
b
-arrestin isoforms in response to agonists or the serotonin precursor,
5HTP.
88-90
In cortical neurons of control animals treated with 5HT,
5HT2A receptors are almost entirely intracellular, whereas in
b
-arrestin 1
and 2-deficient mice, or
b
-arrestin 2 knockout neurons, the receptors are
present at the soma membrane, suggesting a role for arrestins in 5HT2A
receptor trafficking. However, the internalization of receptors following
treatment with the selective 5HT2A receptor agonist, 2,5-dimethoxy-4-
iodoamphetamine (DOI), even in absence of
b
-arrestin isoforms.
From a phenotypic point of view, this interaction between 5HT2A
receptors and
b
-arrestin results in signaling and trafficking processes that lead
to behavior modulation such as head twitching.
71
The head twitch response
induced by 5HTP administration appears to be
b
-arrestin 2 dose dependent.
It fails to reach the wild-type level in
b
-arrestin 2 knockout mice and het-
erozygous mice display an intermediate phenotype.
91
Nevertheless, some
physiological responses to a sudden rise in 5HT level associated with sero-
tonin receptor activation, such as hypothermia and diarrhea, do not differ
between control and
b
-arrestin 2-deficient mice.
91
Other pharmacologic evidence indicates a
b
-arrestin 2-independent
response to hallucinogenic compounds. While 5HTP has impaired efficacy
to produce a head twitch response in
b
-arrestin 2 knockout mice, the
selective hallucinogenic 5HT2A receptor agonist DOI does not show
genotype-dependent efficacy for this behavior.
91
This suggests that while
the head twitch response induced by 5HTP is a
b
-arrestin 2-dependent
behavior, the one induced by DOI is not. This suggests
b
-arrestin 2-
dependent signal transduction downstream of 5HT2A receptors exists
but does not constitute an essential component of this 5HT2A receptor-
modulated behavior.
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