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Corticotropin-releasing
hormone (CRH) is a neuropeptide
secreted abundantly in the
paraventricular nucleus of
the hypothalamus, amygdala,
cerebral cortex and cerebellum
in the central nervous system
It is also expressed in adrenal
gland, placenta, testis,
spleen,
gut, thymus and skin (1).
CRH is the principal mediator
of endocrine stress response
(2).
CRH also plays a significant
role in inflammatory responses
(3, 4), hemodynamic actions
(5), stromal cell decidualization
during estrus cycle (6),
implantation of blastocyst
(7),
maintenance of pregnancy,
onset of labor (8) and neuroprotection
(9). Excess secretion of
CRH during severe depression
and its association with
increased levels of cortisol
have been
observed (10). CRH has also
been reported to be involved
in anxiety disorders (11),
anorexia
nervosa (12). Decrease in
cortical CRH content has
been observed in Alzheimer’s
disease
(13) and Parkinson’s
disease (14).
The actions of CRH are mediated
through class II/secretin-like
family type of G-protein
coupled receptor (GPCR) called
the CRH receptors (CRHR)
(15). CRH is a high affinity
ligand of CRHR1 and also
binds to CRHR2 but with lower
affinity (16, 17). CRH receptors
do not have any intrinsic
kinase activity and transduce
the signal via the heterotrimeric
G-
proteins (18). The CRH receptors
are rapidly desensitized
by G-protein-coupled receptor
kinase (GRK) and ß-arrestin
mechanisms in the presence
of high concentrations of
CRH
(19). Binding of CRH to CRH
receptor induces a conformational
change in the receptor by
activating it. This further
activates Ga-subunit and
its subsequent dissociation
from the Gß?
dimer. CRH receptors on interaction
with Ga-subunit of different
G-proteins such as Gas,
Gai/o, Gaq/11 activate numerous
downstream signaling cascades
and result in the induction
of
various cellular responses
(20). The pathways that are
activated upon CRH stimulation
are:
Adenylate cyclase/cAMP/PKA,
PLC/PKC, ERK/MAPK, PI3K-AKT
and NF-kappa B.
CRH binding to CRHR1 couples
G-stimulatory (Gs) protein
which in turn activates cAMP-
dependent protein kinase
(PKA). Activation of PKA
leads to the phosphorylation
of
transcription factors like
cAMP response element binding
protein (CREB), which in
turn
increases the expression
of pro-opiomelanocortin (POMC)
gene and the release of POMC-
derived peptides, adrenocorticotropic
hormone (ACTH) and ß-endorphin.
ACTH, in turn,
stimulates the secretion
of glucocorticoids from adrenal
glands and thereby mediates
changes
associated with stress response
(2, 21). CREB also regulates
genes containing the Ca 2+/cAMP
response element such as
FOS (9). The activation of
cAMP by CRH induces the mRNA
expression and transcription
of orphan nuclear receptors
NR4A1 and NR4A2, which in
turn
transcriptionally activates
the expression of POMC (20).
Activation of cAMP/PKA can
also
induce the expression of
enzymes involved in dehydroepiandrosterone
sulfate and cortisol
production (22, 23). The
biological functions of CRH
are also mediated by MAPK
family,
in particular MAPK1/3 and
MAPK14. MAPK1/3 mediates
activation of transcription
factors
NR4A1 and NR4A2 and induction
of POMC in corticotrophs
(24). MAPK14 is involved
in
CRH-induced inhibition of
IL-18 expression in human
keratinocytes (25). The CRHR1/PKA/
ERK signaling activate the
transcription factors - ELK1
(26), SP1 and TFAP2A (27).
SP1
and TFAP2A up-regulates the
expression of ADRBK2, which
causes the desensitization
of
CRHR1 receptors (28).
The PLC/PKC pathway is activated
by coupling of the CRH receptors
to the Gaq/11
proteins. This cascade stimulates
the formation of IP3 and
contributes to the mobilization
of intracellular calcium.
Calcium is involved in the
transcription regulation
of FOS as well
as NR4A1 and NR4A2 through
CAMK2A. PLC/PKC is involved
in the activation of AP-
1 complex and subsequent
transcriptional regulation
of genes involved in keratinocyte
differentiation and proliferation – KRT1,
KRT14 and IVL (29). This
cascade also inhibits
the expression of CYP11A1
and HSD3B1, the genes involved
in progesterone synthesis
in
placental trophoblasts (30).
Another important signaling
pathway activated upon CRH
stimulation is the nitric
oxide
(NO)/cGMP, involved in the
control of vascular tone
(31). In human keratinocytes,
upon CRH stimulation, NFKBIA
degradation is diminished
and the activity of NFKB
is
inhibited resulting in the
down-regulation of NFKB-dependant
genes IL2 and HSP90AA1
and inhibition of cell proliferation
(32). The gene involved in
cell survival, BCL2 is
transcriptionally regulated
via the PI3K/AKT (33).
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