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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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