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Fig. 6.4
Model of kisspeptin's actions to depolarize GnRH neurons and facilitate burst fi ring.
Kisspeptin binds to its cognate GPR54 receptor, which is Gq-coupled to activate phospholipase
Cβ. PLCβ has multiple downstream actions resultant from cleaving phosphatidylinositol 4,5
bisphosphate (PIP
2
) to inositol 1,4,5-triphosphate (IP
3
) and diacylglycerol (DAG). Since PIP
2
facilitates Kir channel opening, cleavage of this fatty acid attenuates K-ATP and GIRK channel
opening. Inhibition of GIRK channels renders a number of Gα
i/o
-coupled receptors ineffective
to inhibit GnRH neurons (GABA
B
, μ-opioid, NPY, MCH, etc.). On the other hand, cleavage of
PIP
2
facilitates TRPC 4 channel opening [
126
]. In addition the membrane-associated fatty acid
DAG probably activates the TRPC1, 4, 5 channel complex [Note: The OAG (analogue of DAG)
was only weakly effective to open the TRPC channels since PIP
2
still exerted a strong inhibi-
tion of the TRPC channel complex]. Ca
2+
potentiates the agonist-activated TRPC1, 4, 5 com-
plex, and plasma membrane calcium channels appear to play a critical role. Intracellular 2-APB
dialysis, which effectively blocks IP3 receptor-mediated release of Ca
2+
, was ineffective, but
extracellular Cd
2+
potently inhibited TRPC1, 4, 5 channel activity. Therefore, we propose that
low voltage-activated T-type calcium channels are initially involved in facilitating TRPC chan-
nel opening. Once depolarized, Ca
2+
entry through high voltage-activated Ca
2+
channels can
also contribute to facilitating TRPC channel opening. Also illustrated are other channels con-
tributing to burst fi ring activity such as the hyperpolarization-activated, cyclic nucleotide-gated
(HCN, pacemaker) channel, and the small conductance, Ca
2+
-activated K
+
channel
(SK), which
is involved in the repolarization of the membrane following a burst of action potentials
desensitize (i.e., heterologous desensitization) G
i/o
-coupled receptors through PIP
2
hydrolysis and attenuating the GIRK-mediated hyperpolarization (Fig.
6.4
) [
97
-
99
]. In addition to attenuating G
α
i/o
-coupled receptor-mediated hyperpolarization,
kisspeptin activates TRPC channels in GnRH neurons to cause further depolariza-
tion [
14
]. The Kiss1R-G
α
signaling pathway would have a twofold effect
to inhibit K
+
channels and activate TRPC channels, which underlies the pronounced
excitatory effects of kisspeptin on GnRH neurons [
12
-
14
,
50
,
52
]. Interestingly
MCH, although at higher concentrations, can block kisspeptin excitation of septal
vesicular glutamate transporter 2 (vGluT2)-GnRH neurons by inhibiting Kir [
55
],
which could be a mechanism by which GnRH neuronal excitability is reduced dur-
ing certain physiological states.
α
q/11
-PLC
β
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