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Fig. 7.2
KISS1R signaling in the hypothalamus. Upon kisspeptin binding, G proteins are dissoci-
ated and the G
q/11
subunit activates phospholipase C beta (PLC
β
) to hydrolyze membrane phos-
phatidyl inositol 4,5-biphosphate (PIP
2
), producing inositol triphosphate (IP
3
) and diacylglycerol
(DAG). IP
3
binds to receptors on the endoplasmic reticulum (ER) to release stored calcium (Ca
2+
)
and DAG contributes to the activation of the calcium-dependent protein kinase (PKC). The extra-
cellular regulated kinase (ERK) is one of the PKC-dependent downstream signals of KISS1R.
These signals ultimately lead to increased secretion of GnRH, which then leads to increased LH
secretion
α
GDP, thereby inactivating G
α
, which then binds to G
βγ
again. Dissociated G
αq
stimu-
lates phospholipase C
β
, a membrane-resident enzyme that hydrolyzes phosphati-
dylinositol 4,5-bisphosphate (PIP
2
) to produce the intracellular messengers
diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP
3
) (Fig.
7.2
). Binding of
IP
3
to its receptors on the endoplasmic reticulum causes a massive release of cal-
cium from the intracellular stores into the cytosol, with widespread activation of
calcium-dependent signaling pathways, whereas DAG contributes to activation of
the calcium-dependent protein kinase C (PKC) (Fig.
7.2
). Accordingly, stimulation
of KISS1R with kisspeptin in Chinese hamster ovary (CHO) cells transfected with
the human (or rat) receptor leads to phospholipase C
β
activation, PIP
2
hydrolysis
and intracellular IP
3
accumulation [
37
]. Calcium-dependent signals activated by
KISS1R include kinases such as PKC, the extracellular signal-regulated kinases 1
and 2 (ERK1/2) and the p38-mitogen-activated protein kinase (p38-MAPK) [
44
,
45
].
The stimulatory effect of kisspeptin on GnRH secretion was also shown to require
calcium mobilization, as well as ERK and p38MAPK activation in GnRH neurons
of rats [
46
].
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