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secretion. In turn, ACTH receptor activation in the adrenal cortex modu-
lates the synthesis and release of the steroid hormone, cortisol, an important
mediator of the stress response.
138,139
CRF
1
and CRF
2
receptors mostly differ in their N-terminal domain,
while except for the four last amino acids, their intracellular domains are
highly homologous. This variability at the N-terminus appears to affect
the affinity for and efficacy of CRF.
CRF affinity for CRF
1
receptors is higher than for CRF
2
receptors.
Thus, at a low CRF secretion level, CRF
1
-dependent signaling pathways
are more active than CRF
2
-dependent ones, but both receptors are activated
at high CRF concentrations. The activation of CRF
1
receptors induces
anxiety-like responses which have been widely implicated in affective dis-
orders and major depression,
140
suggesting that CRF
1
receptor antagonists
may prove beneficial in anxiety and depression treatment.
141,142
Surprisingly, the importance of CRF
1
receptors in depressive-like
behaviors seems inconsistent with the results obtained in behavioral despair
tests, such as the Porsolt swim test and tail suspension test. In these tests,
treatment with antidepressant drugs that act on monoamine neurotransmis-
sion reduce immobility, an effect that is interpreted as enhanced motivation
to confront. Contrary to expectations, CRF
1
receptor stimulation via intra-
cerebroventricular injection of a CRF
1
receptor agonist reduces immobil-
ity.
143,144
These differences may be in part explained by the choice of animal
model and the interpretation of results. While in some cases prolonged
immobility can be representative of a depression-like behavior, the same
response could also be interpreted as a diminished stress response.
As with CRF
1
receptors, the
in vivo
role of CRF
2
receptors in stress
and anxiety is controversial. The role in CRF
2
receptors in anxiety
and depressive physiopathology is even less clear. CRF
2
receptor knock-
out mice have an increased or normal anxiety responses, while blocking
receptor pharmacologically can both increase or decrease anxiety-
like response.
138,140,145-147
While some evidence supports the idea that
CRF
2
receptors reestablish homeostasis by counteracting CRF
1
responses,
other theories implicate these receptors in the passive anxiety and depres-
sion response.
148
6.2. CRF receptors and GRK
CRF receptors are widely regulated by arrestins and GRK. The receptor
contains seven putative sites of GRK phosphorylation on the C-terminal
domain that may be involved in
b
-arrestin recruitment. Among the different
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