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Fig. 22.3
Intracellular signalling events in GnRH neurons after kisspeptin stimulation. Kisspeptin
binding to its receptor activates the G-protein G
q/11
to stimulate phospholipase C (PLC) activity and
cleavage of PIP
2
into IP
3
and diacylglycerol (DAG). DAG stimulates canonical transient receptor
potential channels (TRPC) and inhibits voltage
K
v
) to cause membrane
depolarization and action potential fi ring. Intracellular calcium levels are increased by release of
Ca
2+
from endoplasmic reticulum stores (mediated by IP
3
R and RyR3) and also by Ca
2+
infl ux
through TRPC channels. Additional Ca
2+
may also enter the cell after membrane depolarization by
voltage-gated calcium channels (VGCC) which are subsequently inactivated by calmodulin.
PIP
2
phosphatidylinositol 4,5-bisphosphate;
IP
3
inositol triphosphate;
IP
3
R
IP
3
receptor;
RyR3
ryano-
dine receptor 3
-gated potassium channels (
depolarization is caused by inhibition of voltage-gated potassium channels (
K
v
)
[
57
,
58
] and activation of canonical transient receptor potential channels (TRPC)
[
56
,
59
]. Indeed, individual GnRH neurons have been shown by RT-PCR to express
several TRPC channel subunits [
59
]. GnRH neurons also show a rise in intracellu-
lar Ca
2+
after kisspeptin stimulation [
56
]. This rise is due not only to inositol-
(1,4,5)-triphosphate (IP
3
)-mediated Ca
2+
release from the endoplasmic reticulum,
but also to Ca
2+
entry through TRPC channels and Ca
2+
-induced Ca
2+
release via
RyR3 (Fig.
22.3
) [
60
]. Kisspeptin-induced membrane depolarization may also acti-
vate voltage-gated calcium channels (VGCC) to allow additional Ca
2+
entry. The
VGCC channels would be subsequently closed by a Ca
2+
/calmodulin- dependent
feedback loop.
A small number of GnRH neurons (around 2%) show intrinsic oscillations in
membrane potential often accompanied by neuronal fi ring [
61
]. Kisspeptin causes
these neurons to oscillate closer to the depolarization threshold, effectively making
these neurons more sensitive to additional depolarization signals and increasing
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